JP2020527577A - TLR7 / 8 antagonists and their use - Google Patents

Abstract

The present invention relates to compounds of formula I and pharmaceutically acceptable compositions thereof, which are useful as TLR7 / 8 antagonists.

Description

Related Applications This application claims the interests of US Provisional Application No. 62 / 533,820, filed July 18, 2017. The contents of the provisional application are incorporated by reference to the whole.

Technical Fields of the Invention The present invention presents the treatment of compounds of formula (I) as Toll-like receptor 7/8 (TLR7 / 8) antagonists and other diseases associated with immune disorders and TLR7 / 8 overexpression. Provide with their use in.

Background of the Invention Toll-like receptors (TLRs), which currently contain a gene family of 10 receptors with different specificities, are part of the cell's pathogen pattern recognition system, which is associated with a variety of infectious diseases (TLRs). It has evolved to protect against bacteria, viruses, fungi). Activation of TLRs leads to said responses with cytokine responses, such as the release of interferon and activation of specific immune cells. The functional expression of selected TLRs in tissues is very different. Some of the receptors are located on the cell surface, eg on epithelial cells, such as TLR4 (stimulated by E. coli lipopolysaccharide LPS), or TLRs 3, 7, 8 and 9 are It is located on the endosome membrane in specific immune cells. All of the latter are activated by nucleic acids, but recognize different types of nucleic acids. As an example, TLR9 is activated by single-stranded DNA containing a CpG sequence, TLR7 and 8 are activated by single-stranded RNA, and TLR3 is activated by double-stranded RNA.

TLRs are involved in a variety of autoimmune and inflammatory diseases, with TLR7 playing the most obvious role in the pathogenic mechanism of systemic lupus erythematosus (Barrat and Coffman, Immunol Rev, 223: 271). -283, 2008). In addition, TLR8 polymorphisms are associated with rheumatoid arthritis (Enevold et al., J Rheumatol, 37: 905-10, 2010). Although various inhibitors of TLR7, TLR8 and TLR9 have been described, additional TLR inhibitors are desired. In particular, polynucleotides with inhibitory motifs for one or more of TLR7, TLR8 and TLR9 are required to strictly inhibit the immune response in a subject (eg, a patient with an autoimmune disease or inflammatory disorder). It is said that.

The strong efforts to utilize the strong immune activation induced by TLR7, 8 or 9 agonists for the treatment of cancer have continued in recent years as a global attempt. However, cancer immunotherapy has experienced a long history of failure. But in recent years, knowledge of cancer immune surveillance and the resulting function of immune cell subsets has improved dramatically. Agonists of TLR7 or TLR9 are in clinical development for cancer monotherapy or combination therapy, or as a vaccine adjuvant. The TLR agonist approach for cancer immunotherapy differs from previous struggles using cytokines, interferon or monovalent vaccination as an example. Immune activation mediated by TLR agonists is multifaceted via specific immune cells (mainly dendritic cells and B cells, followed by other cells), and said immune activation results in an innate and adaptive immune response. Is done. Moreover, not only one type of interferon, but rather many different isoforms are induced all at once, not only type I (alpha, beta) but also type II (gamma, NK cells) (indirectly). Will be done.

Outline of the present invention In one aspect, the present invention describes the formula (I):
Provided are compounds represented by, and pharmaceutically acceptable derivatives, solvates, salts, hydrates and stereoisomers thereof.

In another aspect, the invention provides a compound of formula (I) that is a dual antagonist of TLR7 and TLR8. In another aspect, the invention provides a compound of formula (I) suitable for the treatment and / or prevention of disorders relating to TLR7 / 8. In another aspect, the invention provides compounds that are capable of modulating, particularly inhibiting, the activity or function of TLR7 / 8 in mammalian, especially human pathology.

According to another aspect of the invention, methods for the treatment and / or prevention of autoimmune disorders are provided.

According to another aspect, the present invention provides a compound represented by the formula (I) selective for TLR7 or TLR8.

According to another aspect, the present invention provides compounds represented by the formula (I) selective for TLR7 and TLR8.

Detailed description of a certain aspect 1. General Description of Compounds of the Invention In certain aspects, the invention provides antagonists of TLR7 / 8. In some embodiments, such compounds include compounds represented by the formulas described herein, or pharmaceutically acceptable salts thereof, wherein each variable is described herein. As defined and described.

2. 2. Compounds and Definitions The compounds of the invention include those generally described above and are further described by the classes, subclasses, and species disclosed herein. As used herein, the following definitions may apply unless otherwise indicated. Purposes, the chemical elements of the present invention, Elements, CAS version, are identified in accordance with the Periodic Table of the ^{Handbook of Chemistry and Physics, 75 th} Ed. In addition, general principles of organic chemistry, "Organic Chemistry", Thomas Sorrell , University Science Books, Sausalito:. 1999, and "March's Advanced Organic Chemistry", 5 th Ed, Ed .: Smith, MB and March, J. , John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

The term "hydrocarbon" or "alicyclic group", as used herein, is a linear chain (ie, a linear chain) that is completely saturated or contains one or more unsaturated units. , Unbranched) or branched, substituted or unsubstituted hydrocarbon chains, or monocyclic or bicyclic hydrocarbons that are completely saturated or contain one or more unsaturated units. As it means, these are not aromatics (also referred to herein as "carbon rings", "alicyclics" or "cycloalkyls") and are the rest of the molecule. ) Has a single point of attachment. Unless so specified, an aliphatic group comprises 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group comprises 1-5 aliphatic carbon atoms. In another embodiment, the aliphatic group comprises 1 to 4 aliphatic carbon atoms. Yet, in another embodiment, the aliphatic group comprises 1 to 3 aliphatic carbon atoms, and in still other embodiments, the aliphatic group comprises 1 to 2 aliphatic carbon atoms. In some embodiments, the "alicyclic" (or "carbon ring" or "cycloalkyl") is a monocyclic C _{3 to} C ₆ that is completely saturated or contains one or more unsaturated units. Refers to hydrocarbons, which are not aromatics and have a single point of attachment to the rest of the molecule. The exemplary aliphatic group is a linear or branched, substituted or unsubstituted C _1- C ₈ alkyl group such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl. , _C 2 -C ₈ alkenyl _group, a C 2 -C ₈ alkynyl and hybrids thereof.

The term "lower alkyl" refers to a C _1-4 linear or branched alkyl group. Illustrated lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

The term "lower haloalkyl" refers to a C _1-4 linear or branched alkyl group substituted with one or more halogen atoms.

The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, or phosphorus (oxidized form of either nitrogen, sulfur, or phosphorus; quaternized form of any basic nitrogen, or; heterocyclic substitutable. Nitrogen, such as N (found in 3,4-dihydro-2H-pyrrolidyl), NH (found in pyrrolidinyl) or NR ⁺ (found in N-substituted pyrrolidinyl).

The term "unsaturated", as used herein, means that an moiety has one or more unsaturated units.

As used herein, the term "divalent C _1-8 (or C _1-6 ) saturated or unsaturated, linear (linear) or branched, hydrocarbon chains" is used. Refers to straight or branched divalent alkylene chains, alkenylene chains, and alquinylene chains as defined herein.

The term "alkylene" refers to a divalent alkyl group. The "alkylene chain" is a polymethylene group, i.e.-(CH ₂ ) _n- , where n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3. 1 to 2, or 2 to 3. The substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

The term "halogen" means F, Cl, Br, or I.

The term "aryl", used alone or as part of the larger portion found in "aralkyl," "aralkoxy," or "aryloxyalkyl," has a total of 5 to 14 ring members. Refers to monocyclic and bicyclic ring systems having (ring members), wherein at least one ring in the system is aromatic, and where each ring in the system is 3-7. Includes individual ring members. The term "aryl" is used interchangeably with the term "aryl ring". In certain aspects of the invention, "aryl" refers to an aromatic ring system. Illustrated aryl groups are phenyl, biphenyl, naphthyl, anthracyl and the like, which optionally include one or more substituents. Also included within the term "aryl", when used herein, are aromatic rings such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc. There are also groups that are condensed with one or more non-aromatic rings.

The terms "heteroaryl" and "heteroar-", used alone or as part of a larger portion, such as "heteroaralkyl" or "heteroararcoxy", are 5 It has 10 ring atoms, preferably 5, 6 or 9 ring atoms; has 6, 10, or 14 π electrons shared in the cyclic array; and in addition to the carbon atom, 1 Refers to a group having 1 to 5 heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes either oxidized form of nitrogen or sulfur, and a quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, indridinyl, prynyl, naphthylidyl. And include pterizinyl. The terms "heteroaryl" and "heteroara" also, as used herein, also include radicals where the heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings. However, here the radical or attachment point is on the heteroaromatic ring. Non-limiting examples are indolyl, isoindrill, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenazinyl. Includes phenoxadinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido [2,3-b] -1,4-oxadin-3 (4H) -one. Heteroaryl groups are optionally mono- or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", but any of these terms may be optionally substituted. Including. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, where the alkyl and heteroaryl moieties may be independently and optionally substituted.

As used herein, the terms "heterocycle", "heterocyclyl", "cyclic radical", and "heterocyclic ring" are used interchangeably and are stable. Refers to a 5- to 7-membered monocyclic or 7 to 10-membered bicyclic heterocyclic moiety, which is either saturated or partially unsaturated, in addition to carbon atoms. It has one or more, preferably 1-4, heteroatoms as defined above. When used with respect to the ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring with 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen is N (found in 3,4-dihydro-2H-pyrrolill), NH (found in pyrrolidinyl), or ⁺ NR (found in N-substituted pyrrolidinyl).

The heterocycle can be attached to the pendant group with a heteroatom or carbon atom, resulting in a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydropyran, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, Includes oxazolidinyl, piperazinyl, dioxanyl, dioxoranyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinucridinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein, they are also used herein. It also includes radicals where the heterocyclyl ring is fused to one or more aryls, heteroaryls, or alicyclics, such as indolinyl, 3H-indrill, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Here the radical or attachment point is on the heterocyclyl ring. Heterocyclyl groups are optionally mono- or bicyclic. The term "heterocyclyl alkyl" refers to an alkyl group substituted with heterocyclyl, where the alkyl and heterocyclyl moieties may be independently and optionally substituted.

As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to cover rings with multi-site unsaturatedity, but may include aryl or heteroaryl moieties as defined herein. Not intended.

Condensed rings are described by aspects of each ring; ring A and ring B, as described herein. Together, ring A and ring B form a condensed heteroaryl ring as allowed by valence (eg, ring A,

And the ring B is

When, the rings A and B are then together,

Is).

As described herein, certain compounds of the invention include "optionally substituted" moieties. In general, the term "substituted" means that one or more hydrogens in a designated moiety have been replaced with a suitable substituent, whether or not preceded by the term "arbitrarily". To do. "Replacement" is the structure (for example,

At least

Point to; and

At least

Applies to one or more hydrogens, either explicit or implied. Unless so indicated, an "optionally substituted" group has a suitable substituent at each substitutable position of the group, and more than one in any given structure. When a position is substituted with more than one substituent selected from a particular group, the substituents are either the same or different at any position. The combination of substituents envisioned by the present invention preferably results in the formation of stable or chemically feasible compounds. The term "stable", when used herein, is their production, detection, in some embodiments recovery, purification, and use of them for one or more purposes disclosed herein. Refers to a compound that does not change substantially when subjected to a state that enables.

Suitable monovalent substituents on substitutable carbon atoms of the "optionally substituted" group are independently heavy hydrogen; halogen;-(CH ₂ ) _0-4 R °;-( _{CH 2) 0~4 OR °; -O} (CH 2) 0~4 R o, -O- (CH 2) 0~4 C (O) OR ° ;-( CH 2) 0~4 CH (OR ° ) ₂ ;-(CH ₂ ) _0-4 SR °; arbitrarily substituted at R °,-(CH ₂ ) _0-4 Ph; arbitrarily substituted at R °,-(CH ₂ ) _0-4 O (CH ₂ ) _{0 to 1} Ph; arbitrarily substituted at R °, −CH = CHPh; arbitrarily substituted at R °, − (CH ₂ ) _{0 to 4} O (CH ₂ ) _{0 to 1} − Pyridil; -NO ₂ ; -CN; -N ₃ ;-(CH ₂ ) _0-4 N (R °) ₂ ;-(CH ₂ ) _0-4 N (R °) C (O) R °; -N (R °) C (S) R °;-(CH ₂ ) _0-4 N (R °) C (O) NR ° ₂ ; -N (R °) C (S) NR ° ₂ ;-(CH ₂₎ ) _0-4 N (R °) C (O) OR °; -N (R °) N (R °) C (O) R °; -N (R °) N (R °) C (O) NR ° ₂ ; -N (R °) N (R °) C (O) OR °;-(CH ₂ ) _0-4 C (O) R °; -C (S) R °;-(CH ₂ ) _{0 ~ 4} C (O) OR °;-(CH ₂ ) _0-4 C (O) SR °;-(CH ₂ ) _0-4 C (O) OSiR ° ₃ ;-(CH ₂ ) _0-4 OC ( O) R °; -OC (O) (CH ₂ ) _0-4 SR °, SC (S) SR °;-(CH ₂ ) _0-4 SC (O) R °;-(CH ₂ ) _0-4 C (O) NR ° ₂ ; -C (S) NR ° ₂ ; -C (S) SR °; -SC (S) SR °,-(CH ₂ ) _0-4 OC (O) NR ° ₂ ;- C (O) N (OR °) R °; -C (O) C (O) R °; -C (O) CH ₂ C (O) R °; -C (NOR °) R °;-(CH) ₂ ) _0-4 SSR °;-(CH ₂ ) _0-4 S (O) ₂ R °;-(CH ₂ ) _0-4 S (O) ₂ OR °;-(CH ₂ ) _0-4 OS ( O) ₂ R °; −S (O) ₂ NR ° ₂ ; − (CH ₂ ) _0-4 S (O) R °; −N (R °) S (O) ₂ NR ° ₂ ; −N (R) °) S (O) ₂ R °; -N (OR °) R °; -C (NH) NR ° ₂ ; -P ( O) ₂ R °; -P (O) R ° ₂ ; -OP (O) R ° ₂ ; -OP (O) (OR °) ₂ ; SiR ° ₃ ;-(C _1-4 linear or branched Alkylene) ON (R °) ₂ ; or-(C _1-4 linear or branched alkylene) C (O) ON (R °) ₂ , where each R ° is , Arbitrarily substituted as defined below, and each R ° is independently hydrogen, C _1-6 aliphatic, -CH ₂ Ph, -O (CH ₂ ) _0-1 Ph,- CH _2- (5-6-membered heteroaryl ring), or saturated, partially unsaturated, or aryl 5-6-membered ring (independently selected from nitrogen, oxygen, or sulfur 0- (Having 4 heteroatoms) or, despite the above definition, 2 independently present in R ° are saturated together with their intervening atoms (s). Forming a partially unsaturated or aryl 3- to 12-membered monocyclic or bicyclic ring (independently having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur). However, these may be optionally replaced as defined below.

Suitable monovalent substituents on R ° (or a ring formed by the combination of two of the independent beings of R ° with their intervening atoms) are independent of dehydrogen, halogen ,-(CH ₂ ) _0-2 R ^l ,-(Halo R ^l ),-(CH ₂ ) _0-2 OH,-(CH ₂ ) _0-2 OR ^l ,-(CH ₂ ) _0-2 CH (CH ₂ ) OR ^l ) ₂ ; -O (halo R ^l ), -CN, -N ₃ ,-(CH ₂ ) _{0 to 2} C (O) R ^l ,-(CH ₂ ) _{0 to 2} C (O) OH,- (CH ₂ ) _{0 to 2} C (O) OR ^l ,-(CH ₂ ) _{0 to 2} SR ^l ,-(CH ₂ ) _{0 to 2} SH,-(CH ₂ ) _{0 to 2} NH ₂ ,-(CH ₂₎ ) _0-2 NHR ^l ,-(CH ₂ ) _0-2 NR ^l ₂ , -NO ₂ , -SiR ^l ₃ , -OSiR ^l ₃ , -C (O) SR ^l ,-(C _1-4 linear or Branched alkylene) C (O) OR ^l , or -SSR ^l , where each R ^l is unsubstituted or, if preceded by a "halo", only with one or more halogens. Unsubstituted, and each R ^l is independently saturated with C _1-4 aliphatic, -CH ₂ Ph, -O (CH ₂ ) _0-1 Ph, or 5-6 members, partially. It is selected from unsaturated or aryl rings (independently having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur). Suitable divalent substituents on saturated carbon atoms at R ° include = O and = S.

Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group are: = O, = S, = NNR ^* ₂ , = NNHC (O) R ^* , = NNHC ( O) OR ^* , = NNHS (O) ₂ R ^* , = NR ^* , = NOR ^* , -O (C (R ^* ₂ )) _2-3 O-, or -S (C (R ^* ₂ )) _{2 Including ~ 3} S-, where each independent presence of R ^* is hydrogen, partially unsaturated, substituted or unsubstituted as defined below, saturated with 5-6 members. It is selected from saturated or aryl rings (independently having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur). Suitable divalent substituents attached to substitutable neighboring carbons of "optionally substituted" groups include: -O (CR ^* ₂ ) _2-3 O-, but here. Each independent presence of R ^* is hydrogen, a 5- to 6-membered saturated, partially unsaturated or aryl ring (independently, substituted or unsubstituted as defined below). It has 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur).

Suitable substituents on the aliphatic group of R ^* are halogen, -R ^l ,-(halo R ^l ), -OH, -OR ^l , -O (halo R ^l ), -CN, -C (O). Includes OH, -C (O) OR ^l , -NH ₂ , -NHR ^l , -NR ^l ₂ , or -NO ₂ , where each R ^l is unsaturated or "halo". Was preceded by one or more halogens, and each R ^l was independently C _1-4 aliphatic, -CH ₂ Ph, -O (CH ₂ ) _0-1 Ph. , Or a 5- to 6-membered, partially unsaturated, or aryl ring (independently having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur).

Suitable substituents on substitutable nitrogen of "optionally substituted" groups are -R ^† , -NR ^† ₂ , -C (O) R ^† , -C (O) OR ^† ,-. C (O) C (O) R ^† , -C (O) CH ₂ C (O) R ^† , -S (O) ₂ R ^† , -S (O) ₂ NR ^† ₂ , -C (S) NR ^{Includes †} ₂ , -C (NH) NR ^† ₂ , or -N (R ^† ) S (O) ₂ R ^† ; where each R ^† is independently hydrogen, as defined below. Arbitrarily substituted C _1-6 aliphatic, unsubstituted -OPh, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl rings (independently, nitrogen). , Oxygen, or sulfur (having 0-4 heteroatoms selected from), or, despite the above definition, two of the independent entities of R ^† are their intervening atoms ( Along with singular or plural), unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic (independently selected from nitrogen, oxygen, or sulfur). (Has 0 to 4 heteroatoms).

Suitable substituents on the aliphatic group of R ^† are independently halogen, -R ^l ,-(halo R ^l ), -OH, -OR ^l , -O (halo R ^l ), -CN,- C (O) OH, -C (O) OR ^l , -NH ₂ , -NHR ^l , -NR ^l ₂ , or -NO ₂ , where each R ^l is unsaturated or or When preceded by a "halo", it is replaced by only one or more halogens, and each R ^l is independently C _1-4 aliphatic, -CH ₂ Ph, -O (CH ₂ ) _{0. With ~ 1} Ph, or 5-6 member saturated, partially unsaturated, or aryl rings (independently having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur) is there.

In certain embodiments, as used herein, the terms "optionally substituted (arbitrarily substituted)", "arbitrarily substituted alkyl", "arbitrarily substituted" arbitrarily substituted alkenyl "," optionally substituted alkynyl ",""Arbitrary substituted carbocyclic", "arbitrary substituted aryl", "arbitrary substituted heteroaryl", "arbitrary substituted heterocyclic", and any other arbitrary substituent are one or two hydrogen atoms on the group. , Or refers to a group substituted or unsubstituted by independent substitution with three or more typical substituents, the typical substituents include, but are not limited to: :
-F, -Cl, -Br, -I, deuterium,
-OH, protected hydroxy, alkoxy, oxo, thiooxo,
-NO ₂ , -CN, CF ₃ , N ₃ ,
-NH ₂ , protected amino, -NH alkyl, -NH alkenyl, -NH alkynyl, -NH cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocyclic, -dialkylamino, -diaryl Amino, -diheteroarylamino,
-O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclic,
-C (O) -alkyl, -C (O) -alkenyl, -C (O) -alkynyl, -C (O) -carbocyclyl, -C (O) -aryl, -C (O) -heteroaryl,- C (O) -heterocyclyl,
-CONH ₂ , -CONH-alkyl, -CONH-alkenyl, -CONH-alkynyl, -CONH-carbocyclyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocyclyl,
-OCO ₂ -alkyl, -OCO ₂ -alkenyl, -OCO ₂ -alkynyl, -OCO ₂ -carbocyclyl, -OCO ₂ -aryl, -OCO ₂ -heteroaryl, -OCO ₂ -heterocyclyl, -OCONH ₂ , -OCONH- Alkyl, -OCONH-alkenyl, -OCONH-alkynyl, -OCONH-carbocyclyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocyclyl,
-NHC (O) -alkyl, -NHC (O) -alkenyl, -NHC (O) -alkynyl, -NHC (O) -carbocyclyl, -NHC (O) -aryl, -NHC (O) -heteroaryl,- NHC (O) -heterocyclyl, -NHCO ₂ -alkyl, -NHCO ₂ -alkenyl, -NHCO ₂ -alkynyl, -NHCO ₂ -carbocyclyl, -NHCO ₂ -aryl, -NHCO ₂ -heteroaryl, -NHCO ₂ -heterocyclyl, -NHC (O) NH ₂ , -NHC (O) NH-alkyl, -NHC (O) NH-alkenyl, -NHC (O) NH-alkenyl, -NHC (O) NH-carbocyclyl, -NHC (O) NH -Aryl, -NHC (O) NH-heteroaryl, -NHC (O) NH-heterocyclyl, NHC (S) NH ₂ , -NHC (S) NH-alkyl, -NHC (S) NH-alkenyl, -NHC ( S) NH-alkynyl, -NHC (S) NH-carbocyclyl, -NHC (S) NH-aryl, -NHC (S) NH-heteroaryl, -NHC (S) NH-heterocyclyl, -NHC (NH) NH ₂ , -NHC (NH) NH-alkyl, -NHC (NH) NH- -alkenyl, -NHC (NH) NH-alkenyl, -NHC (NH) NH-carbocyclyl, -NHC (NH) NH-aryl, -NHC ( NH) NH-heteroaryl, -NHC (NH) NH-heterocyclyl, -NHC (NH) -alkyl, -NHC (NH) -alkenyl, -NHC (NH) -alkenyl, -NHC (NH) -carbocyclyl, -NHC (NH) -aryl, -NHC (NH) -heteroaryl, -NHC (NH) -heterocyclyl,
-C (NH) NH-alkyl, -C (NH) NH-alkenyl, -C (NH) NH-alkynyl, -C (NH) NH-carbocyclyl, -C (NH) NH-aryl, -C (NH) NH-heteroaryl, -C (NH) NH-heterocyclyl,
-S (O) -alkyl, -S (O) -alkenyl, -S (O) -alkynyl, -S (O) -carbocyclyl, -S (O) -aryl, -S (O) -heteroaryl,- S (O) - heterocyclyl _-SO 2 _NH 2, _-SO 2 NH- alkyl, _-SO 2 NH- alkenyl, _-SO 2 NH- alkynyl, _-SO 2 NH- carbocyclyl, _-SO 2 NH- aryl, -SO ₂ NH-heteroaryl, -SO ₂ NH-heterocyclyl,
-NHSO ₂ -alkyl, -NHSO ₂ -alkenyl, -NHSO ₂ -alkynyl, -NHSO ₂ -carbocyclyl, -NHSO ₂ -aryl, -NHSO ₂ -heteroaryl, -NHSO ₂ -heterocyclyl,
-CH ₂ NH ₂ , -CH ₂ SO ₂ CH ₃ ,
-Mono-, di-, or tri-alkylsilyl,
-Alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic, -heterocyclic, polyalkoxyalkyl, polyalkoxy , -Methoxymethoxy, -methoxyethoxy, -SH, -S-alkyl, -S-alkenyl, -S-alkynyl, -S-carbocyclyl, -S-aryl, -S-heteroaryl, -S-heterocyclyl, or methylthio Methyl.

As used herein, the term "pharmaceutically acceptable salt" is used in humans and inferior, without excessive toxicity, irritation, allergic response, etc., within reasonable medical judgment. Refers to those salts that are suitable for use in contact with animal tissues and are commensurate with a reasonable risk-benefit ratio (benefit / risk ratio). Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the invention include suitable inorganic acids and bases as well as those derived from organic acids and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid. , A salt of an amino group formed with an organic acid such as succinic acid or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts are adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, bicarbonate, boric acid, butyric acid, gypsum acid, camphor-sulfonic acid, citric acid, cyclopentane. Propionic acid, digluconic acid, dodecylsulfate, ethanesulfonic acid, formic acid, fumaric acid, glucoheptonic acid, glycerophosphate, gluconic acid, hemisulfate, heptanic acid, hexanoic acid, hydroiodic acid, 2-hydroxy-ethanesulfonic acid, lactobion Acids, lactic acids, lauric acid, lauryl sulfate, malic acid, maleic acid, malonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, nitrate, oleic acid, oxalic acid, palmitic acid, pamoic acid, pectic acid, excess Includes salts of sulfuric acid, 3-phenylpropionic acid, phosphoric acid, pivalic acid, propionic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiosian acid, p-toluenesulfonic acid, undecanoic acid, valeric acid and the like.

Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts, when appropriate, are formed using counterions such as halides, hydroxides, carboxylic acids, sulfuric acids, phosphoric acids, nitrates, lower alkyl sulfonic acids and aryl sulfonic acids. Includes non-toxic ammonium, quaternary ammonium, and amine cations.

Unless so stated, the structures depicted herein are also of all isomers of the structure (eg, enantiomers, diastereomers, and geometric isomers (or conformations). )) Morphology; for example, it also means including the configuration of R and S for each asymmetric center, the double-binding isomers of Z and E, and the conformation of Z and E. Thus, single stereochemical isomers, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or conformations) of the compounds are within the scope of the invention. Unless so stated, all forms of tautomers of the compounds of the invention are within the scope of the invention.

In addition, unless so stated, the structures depicted herein also imply that they include compounds that differ only in the presence of one or more isotopically enriched atoms. .. For example, compounds having the present structure comprising replacement of hydrogen with deuterium or tritium, or replacement of carbon with ¹³ C or ¹⁴ C enriched carbon are within the scope of the present invention. In some embodiments, the group comprises one or more deuterium atoms.

It is also further intended that the compound of formula I comprises its isotope-labeled form. The isotope-labeled form of a compound of formula I is an atom (single) in which one or more atoms of the compound have an atomic mass or mass number that is different from the atomic mass or mass number of normally naturally occurring atoms. ) Or the fact that it is replaced by an atom (s) is identical to this compound. Examples of isotopes that are commercially available and can be incorporated into compounds of formula I by well-known methods are areotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine. For example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ CI, respectively. A pharmaceutically acceptable salt thereof containing the compound represented by the formula I, a prodrug thereof, or one or more of the above-mentioned isotopes and / or other isotopes of other atoms is described in the present invention. Intended to be part. The isotope-labeled compound of formula I can be used in a number of beneficial ways. For example, an isotope-labeled compound of formula I, which incorporates a radioisotope, such as ³ H or ¹⁴ C, is suitable for pharmaceutical and / or substrate tissue distribution assays. These radioisotopes, namely tritium ( ³ H) and carbon-14 ( ¹⁴ C), are particularly preferred due to their ease of preparation and excellent detectability. Heavier isotopes such the incorporation of deuterium ^{(2 H)} to the compound represented by in the formula I is from greater metabolic stability isotopically labeled the compound has a therapeutic benefit. Higher metabolic stability translates directly into increased in vivo half-life or smaller dosages, which under most circumstances represent a preferred embodiment of the invention. Isotope-labeled compounds of formula I facilitate the procedures disclosed in the synthesis schemes and related descriptions in the examples and preparation sections of the text, facilitating isotope-unlabeled reactants. It can usually be prepared by replacing it with an isotope-labeled reactant available in.

Deuterium ^{(2 H)} Further, in the purpose of for manipulating oxidative metabolism of a compound by the primary kinetic isotope effect (the primary kinetic isotope effect), may also be incorporated into the compound of the formula I. The primary dynamic isotope effect is the rate change of the chemical reaction due to the exchange of isotopic nuclei, which in turn is caused by the change in basal energy required for covalent bond formation after this isotope exchange. Is done. The exchange of heavier isotopes usually results in a decrease in the basal energy of the chemical bond, thus causing a decrease in the rate-determining rate of bond breakage. If the bond break occurs in or near the saddle point region along the coordinate of the multi-product reaction, the distribution ratio of the product can be substantially altered. For illustration: deuterium, when combined with non-exchangeable positions to a carbon atom, the speed differences of _k M _/ k D = 2~7 is typical. If this rate difference is successfully applied to a compound of formula I that is susceptible to oxidation, the in vivo profile of this compound can be dramatically modified, resulting in improved pharmacokinetic properties. obtain.

When discovering and developing therapeutic agents, those skilled in the art speculate that many compounds with inferior pharmacokinetic profiles, which can optimize pharmacokinetic parameters while retaining the desired in vitro properties, are susceptible to oxidative metabolism. It is rational to do. The currently available in vitro hepatic microsome assay provides valuable information about the course of this type of oxidative metabolism, which in turn results in formula I with improved stability through resistance to such oxidative metabolism. The rational design of the represented deuterated compound becomes possible. Significant improvements in the pharmacokinetic profile of the compounds of formula I were obtained thereby, with in vivo half-life (t / 2), concentration at maximum therapeutic effect (C _max ), area under the dose response curve. (AUC), and in terms of increase in F; and in terms of reduced clearance, dose and material cost, can be expressed quantitatively.

The following is intended to explain the above: A compound represented by formula I having multiple potential sites of oxidative metabolic attack (eg, a benzyl hydrogen atom and a hydrogen atom bonded to a nitrogen atom) is of a hydrogen atom. Various combinations are prepared as a series of analogs in which some, most or all of these hydrogen atoms are replaced by dehydrogen atoms. The determination of the half-life allows a favorable and correct determination to the extent that the improvement in resistance to oxidative metabolism is improved. Thus, it is determined that the half-life of the parent compound can be extended up to 100% as a result of this type of deuterium-hydrogen exchange.

Deuterium-hydrogen exchange in the compound of formula I can also be used to achieve a favorable modification of the metabolite spectrum of the starting compound in order to reduce or eliminate unwanted toxic metabolites. For example, when toxic metabolites are produced through oxidative carbon-hydrogen (CH) bond cleavage, hydrocarbon analogs greatly reduce the production of unwanted metabolites, even if the particular oxidation is not a rate-determining step. It can be reasonably speculated that it will or will be excluded. Further information on the state of the art for deuterium-hydrogen exchange can be found, for example, at Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326- 3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al., Biochemistry 33 (10) 2927-2937, 1994, and Jarman et al., Carcinogenesis 16 (4), 683-688 Can be found in, 1993.

As used herein, the term "modulator" is defined as a compound that binds to or / or inhibits a target with measurable affinity. In some embodiments, the modulator is less than about 50 [mu] M, less than about 1 [mu] M, less than about 500 nM, less than about 100 nM, or about _{IC 50} and / or binding constant of less than 10 nM.

The terms "measurable affinity" and "measurable inhibition", as used herein, refer to a sample comprising a compound of the invention or a composition thereof and TLR7 / 8 (and the compound or composition thereof). Means a measurable change in TLR7 / 8 activity between (equivalent sample) containing TLR7 / 8 in the absence of.

The combination of substituents and variants envisioned by the present invention is the only one that results in the formation of stable compounds. The term "stable", when used herein, has sufficient stability to enable manufacture and is an object as detailed herein (eg, to a subject). Refers to a compound that maintains the integrity of the compound for a sufficient period of time useful for therapeutic or prophylactic administration.

The enumeration of a list of chemical groups in any definition of atypical herein includes the definition of that variant as either a single group or a combination of groups in the list. The enumeration of aspects for variants herein includes those aspects either as a single aspect or in combination with any other aspect or parts thereof.

3. 3. Description of Exemplified Compounds According to one aspect, the present invention relates to formula I,

Provided are compounds represented by, or pharmaceutically acceptable salts thereof, in the formula:
Ring A is an aryl, or a heteroaryl having 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, and sulfur); each of them may be optionally substituted. ;
Ring B is a heteroaryl having 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, and sulfur); each of them may be optionally substituted;
R ¹ is -CH ₃ , -CF ₃ , or -CN;
Each R ² independently has -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C (O) R, -CO. ₂ R, -C (O) N (R) ₂ , -NRC (O) R, -NRC (O) N (R) ₂ , -NRSO ₂ R, or -N (R) ₂ ;
Each R ³ independently has -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C (O) R, -CO. ₂ R, -C (O) N (R) ₂ , -NRC (O) R, -NRC (O) N (R) ₂ , -NRSO ₂ R, or -N (R) ₂ ;
Each R ⁴ independently has -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C (O) R, -CO. ₂ R, -C (O) N (R) ₂ , -NRC (O) R, -NRC (O) N (R) ₂ , -NRC (O) OR, -NRSO ₂ R, or -N (R) ₂ ;
Each R ⁵ independently has -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C (O) R, -CO. ₂ R, -C (O) N (R) ₂ , -NRC (O) R, -NRC (O) N (R) ₂ , -NRSO ₂ R, or -N (R) ₂ ;
Each R is independently hydrogen, C _1-6 aliphatic, C _3-10 aryl, 3-8 member saturated or partially unsaturated carbocycles, 1 to 4 heteroatoms (independently, nitrogen). , Oxygen, or sulfur) with 3-7 members, or 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur) with 5-6 members Is a monocyclic heteroaryl ring; each of them may be optionally substituted; or two R groups on the same atom, together with the atom to which they are attached, C. _3- to 7-membered hetero with 3 to ₁₀ aryl, _3- to 8-membered saturated or partially unsaturated carbocycles, 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur) It forms a ring, or a 5- to 6-membered monocyclic heteroaryl ring with 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of them is optional. May be replaced;
k is 0, 1 or 2;
n is 0, 1, or 2;
p is 0, 1, or 2;
r is 1, 2, or 3; and t is 1, 2, or 3.
Here, k is 0 when connected to nitrogen; and k is 1 or 2 when connected to carbon.

In some embodiments, R ¹ is −CH ₃ .

In some embodiments, R ¹ is -CF ₃ .

In some embodiments, R ¹ is -CN.

In some embodiments, k is 0 and R ¹ is absent.

In some embodiments, ring A is phenyl, or a 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur).

In some embodiments, Ring A is phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridadinyl, or triazinyl.

In some embodiments, ring A is phenyl or pyridyl.

In some embodiments, the ring A is

Is.

In some embodiments, the ring A is

Is.

In some embodiments, the ring A is
Is.

In some embodiments, the ring A is
Is.

In some embodiments, the ring A is
Is.

In some embodiments, the ring A is
Is.

In some embodiments, the ring A is
Is.

In some embodiments, ring B is a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, and sulfur).

In some embodiments, Ring B is pyridyl, pyrimidyl, pyrazinyl, pyridadinyl, triazinyl, pyrrole, imidazole, isoxazole, oxazole, or thiazole; each of them may be optionally substituted.

In some embodiments, ring B is pyridyl, pyrazinyl, or pyrrole; each of them may be optionally substituted.

In some embodiments, the ring B is

Is.

In some embodiments, the ring B is

Is.

In some embodiments, the ring B is
Is.

In some embodiments, the ring B is
Is.

In some embodiments, the ring B is
Is.

In some embodiments, each R ² is independently −H.

In some embodiments, each R ² is an independently C _1-6 aliphatic, C _3-10 aryl, 3-8 member saturated or partially unsaturated carbocyclic ring, 1-4. A 3- to 7-membered heterocyclic ring with a heteroatom (independently selected from nitrogen, oxygen, or sulfur), or 1 to 4 heteroatoms (independently from nitrogen, oxygen, or sulfur) It is a 5- to 6-membered monocyclic heteroaryl ring having (selected); each of them may be optionally substituted.

In some embodiments, each R ² is independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl. Each of them may be optionally substituted.

In some embodiments, each R ² is independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0] bicyclooctanyl, [4.3. 0] bicyclononanyl, [4.4.0] bicyclodecanyl, [2.2.2] bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl , Benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisooxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl , Decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydroflo [2,3-b] tetrahydrofuran, flanyl, frazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indridinyl, indolyl, 3H-indyl, isoindolinyl, isoindrenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindyl, isoquinolinyl, isothiazolyl, isooxazolyl, morpholinyl, naphthizinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1, 2,4-Oxaziazolyl; -1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazoridinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoki Satiynyl, phenoxadinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, pteridinyl, prynyl, pyrazinel, pyrazinyl, pyrazolydinyl, pyrazolinyl, pyrazolyl, pyridadinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyridothiazole, pyrridinyl 2H-pyrrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolidinyl, quinoxalinyl, quinucridinyl, tetrahydropyranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiadinyl, 1 , 2,3-Thiadiazolyl, 1,2,4-Thiadiazolyl, 1,2,5-Thiadiazolyl, 1,3,4-Thiadiazolyl, Thianthrenyl, Thiazolyl, Thienyl, Thienothiazolyl, Thienooxazolyl, Thienoimidazolyl, Thiophenyl, Triazinyl , 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of them is optionally substituted. It may have been.

In some embodiments, each R ² independently contains a halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C (O) R, -CO ₂ R, -C (O) N (R) ₂ , -NRC (O) R, -NRC (O) N (R) ₂ , -NRSO ₂ R, or -N (R) ₂ .

In some embodiments, each R ³ is independently −H.

In some embodiments, each R ³ is an independently C _1-6 aliphatic, C _3-10 aryl, 3-8 member saturated or partially unsaturated carbocyclic ring, 1-4. A 3- to 7-membered heterocyclic ring with a heteroatom (independently selected from nitrogen, oxygen, or sulfur), or 1 to 4 heteroatoms (independently from nitrogen, oxygen, or sulfur) It is a 5- to 6-membered monocyclic heteroaryl ring having (selected); each of them may be optionally substituted.

In some embodiments, each R ³ is independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl. Each of them may be optionally substituted.

In some embodiments, each R ³ independently comprises phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0] bicyclooctanyl, [4.3. 0] bicyclononanyl, [4.4.0] bicyclodecanyl, [2.2.2] bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl , Benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisooxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carborinyl, chromanyl, chromenyl, cinnolinyl, decahydroki Norinyl, 2H, 6H-1,5,2-dithiazinyl, dihydroflo [2,3-b] tetrahydrofuran, furanyl, frazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, isoindolenyl, indolinyl, indridinyl, indrill, 3H-indrill , Isoindolinyl, Isoindrenyl, Isobenzofuranyl, Isochromanyl, Isoindazolyl, Isoindolinyl, Isoindyl, Isoquinolinyl, Isothiazolyl, Isooxazolyl, Morphorinyl, Naftyridinyl, Octahydroisoquinolinyl, Oxaziazolyl, 1,2,3-oxadiazolyl, 1,2,4 -Oxaziazolyl; -1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxatinyl, phenoxadinyl, Tetrahydropyran, piperazinyl, piperidinyl, pteridinyl, prynyl, pyranyl, pyrazinyl, pyrazolydinyl, pyrazolinyl, pyrazolyl, pyridadinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolidyl Kinazolinyl, quinolinyl, 4H-quinolidinyl, quinoxalinyl, quinuclidinyl, tetrahydropyran, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiazolizoli Le, 1,2,4-thiazolyl, 1,2,5-thiazolyl, 1,3,4-thiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinel, 1,2, 3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of them may be optionally substituted. ..

In some embodiments, each R ³ is independently halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C (O) R, -CO ₂ R, -C (O) N (R) ₂ , -NRC (O) R, -NRC (O) N (R) ₂ , -NRSO ₂ R, or -N (R) ₂ .

In some embodiments, each ^{R 4} is independently -H.

In some embodiments, each R ⁴ is independently C _1-6 aliphatic, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C (O). R, -CO ₂ R, -C (O) N (R) ₂ , -NRC (O) R, -NRC (O) N (R) ₂ , -NRC (O) OR, -NRC (O) OR, -NRSO ₂ R, or -N (R) ₂ .

In some embodiments, each R ⁴ is independently C _1-6 aliphatic, -OR, -C (O) R, -CO ₂ R, -C (O) N (R) ₂ , -NRC (O). R, -NRC (O) OR, -NRC (O) N (R) ₂ , -NRSO ₂ R, or -N (R) ₂ ; each of them may be optionally substituted.

In some embodiments, each R ⁴ is independently a C _1-6 aliphatic, -C (O) N (R) ₂ , -NRC (O) R, or -N (R) ₂ ; each of them. May be optionally replaced.

In some embodiments, each R ⁴ is independently

Is.

In some embodiments, each ^{R 5} is independently -H.

In some embodiments, each R ⁵ is independently a halogen, C _1-6 aliphatic, C _3-10 aryl, 3-8 member saturated or partially unsaturated carbocyclic ring, 1-4. A 3- to 7-membered heterocyclic ring with 1 heteroatom (independently selected from nitrogen, oxygen, or sulfur), or 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur). It is a 5- to 6-membered monocyclic heteroaryl ring (selected from sulfur); each of them may be optionally substituted.

In some embodiments, each R ^5, independently methyl, ethyl, propyl, i- propyl, butyl, s- butyl, is t- butyl, straight-chain or branched pentyl or straight or branched hexyl, ; each of which may be optionally substituted; or each ^{R 5} is independently -F, -Cl, -Br or -I,.

In some embodiments, each ^{R 5,} independently methyl, ethyl, -F, is -Cl or -Br,.

In some embodiments, each R ⁵ is independent.

Is.

In some embodiments, each of Ring A, Ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , k, n, p, r, and t is defined above, and above and herein. As described alone or in combination in aspects, classes and subclasses.

In some embodiments, the present invention describes the formula I-a.
Provided are compounds represented by, or pharmaceutically acceptable salts thereof, each of R, R ¹ , R ⁴ , R ⁵ , r, and t in the formula being defined above, and above and herein. As described alone or in combination in aspects, classes and subclasses of the book.

In some embodiments, the present invention relates to Formula I-b.
It provides a compound represented by or a salt thereof pharmaceutically acceptable, ^wherein each of ^{R 2, R 3, R 4} , R 5, n, p, r, and t are defined above, And as described above and in aspects, classes and subclasses herein, alone or in combination.

In some embodiments, the present invention describes the formula Ic.
It provides a compound represented by or a salt thereof pharmaceutically acceptable, ^wherein each of ^{R 2, R 3, R 4} , R 5, n, p, r, and t are defined above, And as described above and in aspects, classes and subclasses herein, alone or in combination.

In some embodiments, the present invention provides. Formula I-c
It provides a compound represented by or a salt thereof pharmaceutically acceptable, ^wherein each of ^{R 1, R 2, R 3} , R 4, R 5, k, n, p, r, and t are As defined above and described above and in aspects, classes and subclasses herein, alone or in combination.

In some embodiments, the present invention describes the formula Id.
It provides a compound represented by or a salt thereof pharmaceutically acceptable, ^wherein each of ^{R 1, R 2, R 3} , R 4, R 5, k, n, p, r, and t are As defined above and described above and in aspects, classes and subclasses herein, alone or in combination.

In some embodiments, the present invention provides. Compound represented by formula I-e
It provides a compound represented by or a salt thereof pharmaceutically acceptable, ^wherein each of ^{R 1, R 2, R 3} , R 4, R 5, k, n, p, r, and t are As defined above and described above and in aspects, classes and subclasses herein, alone or in combination.

In some embodiments, the present invention provides compounds selected from Table 1.
Table 1

In some embodiments, the invention provides one selected from the compounds depicted above, or a pharmaceutically acceptable salt thereof.

Depictions of various structures may indicate heteroatoms without attached groups, radicals, charges, or counterions. Those skilled in the art are aware that such depictions are intended to indicate that heteroatoms are attached to hydrogen. (As an example,

Is

Is understood to be).

In some embodiments, the compounds of the invention were synthesized according to the scheme provided in the example below.

4. Use, Formulation and Administration According to other aspects, the invention is a compound of the invention or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier. , Adjuvants, or compositions comprising vehicles. The amount of the compound in the composition of the present invention is such that it is effective in inhibiting TLR7 / 8 or a mutant thereof to a measurable degree in a biological sample or in a patient. In some embodiments, the amount of the compound in the composition of the invention is such that it is effective in measurable inhibition of TLR7 / 8 or a mutant thereof in a biological sample or in a patient. In some embodiments, the compositions of the invention are formulated for administration to a patient in need of such composition.

The term "patient" or "subject" as used herein means an animal, preferably a mammal, most preferably a human.

The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compounds formulated with it. The pharmaceutically acceptable carriers, adjuvants or vehicles used in the compositions of the present invention include ion exchangers, serum proteins such as alumina, aluminum stearate, lecithin, human serum albumin, buffers such as phosphate, glycine. , Sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, These include magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacryllate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and wool fat. Not limited to.

A "pharmaceutically acceptable derivative" can provide a compound of the invention or an inhibitory active metabolite or residue thereof, either directly or indirectly, upon administration to a recipient. Means any non-toxic salt, ester, ester salt or other derivative of the compounds of the invention.

The compositions of the present invention are orally, parenterally, by inhalation spray, locally, rectally, nasally, buccally, vaginal. , Or via an implanted reservoir. The term "parenteral", as used herein, is subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrathecal, intrathecal. Includes injection or infusion techniques, intrahepatic, intralesional, and intracranial. Preferably, the composition is administered orally, intraperitoneally, or intravenously. Sterilized injectable forms of the compositions of the present invention include aqueous or greasy suspensions. These suspensions are formulated according to techniques known in the art using suitable dispersants or wetting and suspending agents. Sterile injectable preparations are also available as sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, even as solutions in 1,3-butanediol. Good. Of the acceptable vehicles and solvents employed, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils have traditionally been employed as solvents or suspension media.

For this purpose, any bland fixed oil employed comprises synthetic mono- or di-glycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, such as natural pharmaceutically acceptable oils such as olive oil or castor oil (particularly their polys). Oxyethylated type). Solutions or suspensions of these oils are also used in the formulation of long chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants (in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions). Also commonly used). Other commonly used surfactants such as Tween, Span and other emulsifiers or bioavailability enhancers are also used in the production of pharmaceutically acceptable solids, liquids, or other dosage forms. Although commonly used, it is used for formulation purposes.

The pharmaceutically acceptable compositions of the present invention are administered orally in any of the orally acceptable dosage forms. Illustrated oral dosage forms are capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. Useful diluents for oral administration in capsule form include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and suspending agent. If desired, certain sweeteners, flavors or colorants are also optionally added.

Alternatively, the pharmaceutically acceptable compositions of the present invention are administered in the form of suppositories for transrectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient, where the excipient is solid at room temperature but liquid at rectal temperature, rectal. Will melt in and release the drug. Such materials include cocoa butter, beeswax and polyethylene glycol.

The pharmaceutically acceptable compositions of the present invention are also topical, especially when the target of treatment, including diseases of the eye, skin, or lower intestinal tract, comprises an area or organ readily accessible by topical application. It is also administered. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be accomplished with transrectal suppository formulations (see above) or with suitable enema formulations. Topically percutaneous patches are also used.

The pharmaceutically acceptable compositions provided for topical application are formulated into suitable ointments containing active components suspended or dissolved in one or more carriers. Examples of carriers for topical administration of this compound are mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified petrolatum and water. Alternatively, the pharmaceutically acceptable composition provided may be formulated into a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The pharmaceutically acceptable compositions of the present invention are optionally administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations and are prepared according to solutions in saline, benzyl alcohol or other suitable preservatives to be employed, bioavailability-enhancing promoters, fluorination. Prepared as carbon and / or other conventional solubilizers or dispersants.

The pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

The amount of compound of the invention optionally combined with the carrier material to produce a single dosage form composition will vary depending on the host being treated and the specific mode of administration. .. Preferably, the provided compositions should be formulated so that a dosage of 0.01-100 mg / kg body weight / day of the compounds can be administered to the patient receiving these compositions. ..

Specific dosages and treatment regimens for any particular patient will employ specific compound activity, age, weight, overall health, gender, diet, time of administration, rate of excretion It should also be understood that it will depend on various factors, including the combination of drugs, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the compound of the invention in the composition will also depend on the specific or compound in the composition.

Use of Compounds and Pharmaceutically Acceptable Compositions The present invention further relates to methods for treating a subject suffering from a TLR7 / 8 related disorder, wherein the method of the compounds represented by Formula I and related formulas. It comprises administering an effective amount to the subject.

The compounds of the present invention are useful as anti-cancer agents for cancers that respond to TLR7 activation. In some embodiments, the cancer is breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine gland, esophagus, endometrial, germ cells, head and neck, kidney, liver, lung. , Laryngeal and hypopharyngeal, mesopharyngeal tumor, sarcoma, ovary, pancreas, prostate, rectum, kidney (renal), small intestine, soft tissue, testis, stomach, skin, urinary tract, vaginal and genital cancer; , Retinal blastoma and Wilms tumor; leukemia, lymphoma, non-Hodgkin's disease, chronic and acute myeloid leukemia, acute lymphoblastic leukemia, Hodgkin's disease, multiple myeloma and T-cell lymphoma; myelodystrophy syndrome, Includes, but is not limited to, plasma cell neoplasms, tumor-associated syndromes, cancers of unknown primary sites and AIDS-related malignancies.

In some embodiments, the compounds of the invention are used to treat cancer of the skin or kidney. The sensitivity of a given cancer to activation of TLR7 is not limited to these, but is a measurement of reduction (slightly reduced, partially reduced or completely reduced) tumor load of primary or metastatic tumors, blood images. Altered, altered blood levels of hormones or cytokines, inhibition of further increase in tumor cell mass, stabilization of disease in patients, assessment of disease-related biomarkers or surrogate markers, extended overall survival of patients (prolonged overall survival), extended time to disease progression of the patient, extended survival without progression of the patient, extended survival without disease of the patient, improved quality of life of the patient, or disease Modulation of comorbidities (eg, but not limited to, pain, sickness, mobilization, hospitalization, altered blood picture, weight loss, wound healing, fever) can be assessed.

The compounds according to the invention are also useful as immune response modifiers that can modulate the immune response from a number of different angles, thereby making them useful in the treatment of various disorders. There may be.

Provided herein comprises administering to an individual an effective amount of an inhibitor of TLR7 and / or TLR8 (eg, a TLR inhibitor) using a compound as described herein. It is a method of inhibiting an individual's immune response. In some variations, TLR inhibitors inhibit the TLR7-dependent immune response. In some variants, TLR inhibitors block the TLR8-dependent immune response. In some variants, TLR inhibitors inhibit TLR7-dependent and TLR8-dependent immune responses. In some variants, TLR inhibitors block TLR7-dependent, TLR8-dependent, and other TLR-dependent immune responses. Unless noted as such, the term TLR inhibitor refers to any one of the TLR inhibitors disclosed herein. In some preferred embodiments, the individual is a human patient.

Methods of immunomodulation are provided by the present disclosure and include those that suppress and / or inhibit an immune response, including but not limited to the immune response. The disclosure also provides methods for ameliorating symptoms associated with unwanted immune activation, including but not limited to those associated with autoimmunity. Immunosuppression and / or inhibition by the methods described herein may be practiced in individuals including individuals suffering from disorders associated with unwanted activation of the immune response. The disclosure also provides a method for inhibiting a response induced by TLR7 and / or TLR8 (eg, in vitro or in vivo). In some variants, cells are contacted with TLR inhibitors in an amount effective to block the response from cells that contribute to the immune response.

Inhibition of TLR7 and / or TLR8 is useful in treating and / or preventing various diseases or disorders that respond to cytokines. Conditions in which TLR7 and / or TLR8 inhibitors may be used as treatment include, but are not limited to, autoimmune diseases and inflammatory disorders. Provided herein are methods of treating or preventing a disease or disorder in an individual, comprising administering to the individual an effective amount of an inhibitor of TLR7 and / or TLR8. Further provided are methods for ameliorating disease or disorder-related symptoms, including administering effective amounts of TLR7 and / or TLR8 inhibitors to an individual with the disease or disorder. Methods for preventing or delaying the onset of a disease or disorder are also provided herein, but the method comprises using an effective amount of one or more inhibitors of TLR7 and / or TLR8 to treat the disease or disorder. Includes administration to individuals with. In some embodiments, the inhibitor is a compound as described herein.

Provided herein are methods of inhibiting an immune response in an individual, wherein the method is in an amount effective in inhibiting the immune response in an individual, at least one as disclosed herein. Includes administration of a species of TLR inhibitor to an individual. In some variants, the immune response is associated with autoimmune disease. In a further aspect, inhibiting the immune response here restores one or more symptoms of an autoimmune disease. Yet in a further aspect, inhibiting the immune response here treats an autoimmune disease. In a further aspect, inhibiting the immune response here prevents or delays the development of autoimmune diseases. In some variants, TLR inhibitors block the TLR7-dependent immune response. In some variants, TLR inhibitors block the TLR8-dependent immune response. In some variants, TLR inhibitors inhibit TLR7-dependent and TLR8-dependent immune responses. In some aspects, at least one TLR inhibitor is administered in an amount effective to inhibit an immune response in an individual.

Also provided herein is a method of treating or preventing an autoimmune disease in an individual, which comprises administering to the individual an effective amount of TLR7 and / or TLR8 inhibitor. In some aspects, autoimmune diseases are characterized by arthralgia, antinuclear antibody positivity, buccal rash, or discoid rash. In some aspects, autoimmune diseases are associated with skin, muscle tissue, and / or connective tissue. In some embodiments, the autoimmune disease is not visible in the individual from the symptoms of skin, muscle tissue, and / or connective tissue. In some embodiments, the autoimmune disease is systemic. Autoimmune diseases include, but are not limited to, rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), systemic erythematosus (SLE), type I diabetes (diabetes mellitus), multiple sclerosis (MS), and antiphosphorus. Lipid syndrome (APS), sclerosing cholangitis, systemic onset arthritis, irritable bowel disease (IBD), scleroderma, Sjogren's disease, leukoplakia, polymyelitis, vulgaris vulgaris, deciduous cystitis, Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, autoimmune hepatitis, pituitary dysfunction, transplant-to-host disease (GvHD), autoimmune skin disease, vasculitis, malignant anemia, and secondary Includes hypothyroidism. Autoimmune diseases may also include, without limitation, multiple vasculitis duplication syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cold disease.

In some aspects, autoimmune diseases are selected from the group consisting of arthritis, pancreatitis, mixed connective tissue disease (MCTD), lupus, antiphospholipid syndrome (APS), systemic arthritis, and irritable bowel syndrome. Will be done.

In another aspect, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune skin disease, and multiple sclerosis.

In another aspect, the autoimmune disease is selected from the group consisting of pancreatitis, glomerulonephritis, pyelonephritis, sclerosing cholangitis, and type I diabetes. In some aspects, the autoimmune disease is rheumatoid arthritis. In some aspects, the autoimmune disease is autoimmune pancreatitis (AIP). In some aspects, the autoimmune disease is glomerulonephritis. In some aspects, the autoimmune disease is pyelonephritis. In some aspects, the autoimmune disease is sclerosing cholangitis. In some aspects, the autoimmune disorder is psoriasis. In some aspects, the autoimmune disease is a rheumatism-like disease or disorder. In some aspects, the rheumatoid disease or disorder is rheumatoid arthritis. In some aspects, the disease is diabetes and / or diabetes-related disease or disorder. In some aspects, the autoimmune disease here is associated with an RNA-containing immune complex. In some aspects, the autoimmune disease is Sjogren's disease.

Provided herein are methods of inhibiting an immune response in an individual, wherein the method inhibits an immune response in an individual with at least one TLR inhibitor as disclosed herein. Includes administration to an individual in an effective amount. In some variants, the immune response is associated with inflammatory disorders. As used herein, the term "inflammatory disorder" covers an inflammatory condition without known autoimmune components (eg, atherosclerosis, asthma, etc.). In a further aspect, inhibiting the immune response restores one or more symptoms of inflammatory disorders. Still in a further aspect, inhibiting the immune response treats inflammatory disorders. In a further aspect, inhibiting the immune response prevents or delays the onset of inflammatory disorders. In some aspects, the inflammatory disorder is selected from the group consisting of non-rheumatoid arthritis, renal fibrosis, and liver fibrosis. In some aspects, the inflammatory disorder is interfacial dermatitis. In some additional aspects, interfacial dermatitis is lichen planus, lichen planus, lichen planus-like keratosis, linear lichen, chronic lichen keratosis, polymorphic erythema, fixed drug eczema, Lichen planus, phototoxic dermatitis, radioactive dermatitis, viral rash, dermatitis, second-stage syphilis, sclerosing atrophic lichen, fungal sarcoma, lichen planus, lichen planus , Sweat keratosis, chronic atrophic lichen planus, and regressing melanoma. In some aspects, the inflammatory condition is a skin disorder such as atopic dermatitis (eczema). In some aspects, inflammatory disorders are aseptic inflammatory conditions such as drug-induced liver and / or pancreatic inflammation. In some additional aspects, the inflammatory disease is inflammatory liver damage. In some other additional aspects, the inflammatory disease is an inflammatory pancreatic disorder.

Provided herein are methods of inhibiting an immune response in an individual, wherein the method inhibits an immune response in an individual with at least one TLR inhibitor as disclosed herein. Includes administration to an individual in an effective amount. In some variants, the immune response is associated with chronic pathogen stimulation. In some variants, the immune response is associated with HIV infection. In a further aspect, inhibiting the immune response here relieves the symptoms of one or more of the viral diseases or disorders resulting from HIV infection. Yet in a further aspect, inhibiting the immune response here treats a viral disease or disorder resulting from HIV infection. In a further aspect, inhibiting the immune response here prevents or delays the development of viral diseases or disorders resulting from HIV infection. Other variants provided herein relate to immunosuppressive treatment of individuals exposed to or infected with HIV. Administration of TLR inhibitors to individuals exposed to or infected with HIV results in suppression of HIV-induced cytokine production. In some aspects, at least one TLR inhibitor is administered in an amount effective in suppressing HIV-induced cytokine production in individuals exposed to or infected with HIV.

Provided herein are methods for inhibiting a TLR7 and / or TLR8-dependent immune response in an individual, wherein the TLR inhibitor is effective in inhibiting the immune response in an individual. Including administration to an individual in a large amount. In some variants, the immune response is associated with autoimmune disease. In some aspects, the autoimmune disease is rheumatoid arthritis. In some aspects, TLR inhibitors are effective in suppressing one or more symptoms of rheumatoid arthritis. In some aspects, the autoimmune disease is multiple sclerosis. In some aspects, TLR inhibitors are effective in suppressing one or more symptoms of multiple sclerosis. In some aspects, the autoimmune disease is lupus. In some aspects, TLR inhibitors are effective in suppressing one or more symptoms of lupus. In some aspects, the autoimmune disease is pancreatitis. In some aspects, TLR inhibitors are effective in suppressing one or more symptoms of pancreatitis. In some aspects, the autoimmune disease is diabetes. In some aspects, TLR inhibitors are effective in suppressing one or more symptoms of diabetes. In some aspects, the disease is Sjogren's disease. In some aspects, TLR inhibitors are effective in suppressing one or more symptoms of Sjogren's disease. In some variants, the immune response is associated with inflammatory disorders. In some aspects, TLR inhibitors are effective in suppressing one or more symptoms of inflammatory disorders. In some variants, the immune response is associated with chronic pathogen stimulation. In some aspects, TLR inhibitors are effective in suppressing one or more symptoms of chronic pathogen stimulation. In some variants, the immune response is associated with viral disease resulting from infection with HIV. In some aspects, TLR inhibitors are effective in suppressing one or more symptoms of viral disease resulting from infection with HIV. In any variant, the TLR inhibitor is a polynucleotide containing an inhibitory motif for one or more of TLR7, TLR8, and TLR9.

In some aspects of any of the methods involving administration of a TLR inhibitor to an individual (eg, a method of inhibiting an immune response, treating or preventing an autoimmune disease or inflammatory disorder, etc.), a TLR. Inhibitors have a therapeutically acceptable safety profile. TLR inhibitors have a therapeutically acceptable histological profile that includes, for example, an acceptablely low (if any) toxicity of the liver, kidney, pancreas, or other organ. Occasionally, polynucleotides are associated with toxicity to certain organs such as the liver, kidneys and pancreas. In some embodiments, the TLR inhibitor has an unpredictable and advantageous safety profile. In some embodiments, the safety profile comprises assessing toxicity, histological profile, and / or necrosis (eg, liver, kidney and / or heart). In some embodiments, the TLR inhibitor has a therapeutically acceptable level of toxicity. In some embodiments, the TLR inhibitor has a reduced level of toxicity compared to other TLR inhibitors. In some embodiments, the TLR inhibitor induces a therapeutically acceptable reduction in body weight as compared to the initial weight of the treated individual. In some embodiments, the TLR inhibitor induces a reduction of less than 5%, 7.5%, 10%, 12.5, or 15% in total body weight. In some embodiments, the TLR inhibitor has a therapeutically acceptable histological profile. In some embodiments, the TLR inhibitor has a better (eg, lower severity score) histological profile as compared to, for example, a reference TLR inhibitor. In some embodiments, the TLR inhibitor has a better (eg, lower severity score) histological profile, for example, when assessing the liver, kidneys and / or heart. In some embodiments, the TLR inhibitor has a therapeutically acceptable necrosis score. In some embodiments, the TLR inhibitor has reduced necrosis and / or better (eg, lower) necrosis score as compared to, for example, a reference TLR inhibitor. In some embodiments, the TLR inhibitor has a reduced renal and / or hepatocyte necrosis score and / or a better hepatocyte and / or hepatocyte necrosis score as compared to, for example, a reference TLR inhibitor. Has.

As a result, the present invention provides a method of activating TLR7 in animals, especially mammals, preferably humans, wherein the method administers an effective amount of a compound of formula I to the animal. Including. As with all compositions for inhibiting the immune response, the specific effective amount of the TLR inhibitor formulation and the method of administration thereof will be one of ordinary skill in the art, what condition is to be treated. Can fluctuate based on other obvious factors. The effective amount of the compound will vary according to factors known in the art, but will vary from about 0.1 to 10 mg / kg, 0.5 to 10 mg / kg, 1 to 10 mg / kg, 0.1 to 0.1. A dose of 20 mg / kg, 0.1 to 20 mg / kg, or 1 to 20 mg / kg is expected.

The present invention also provides a method of treating a viral infection in an animal, comprising administering to the animal an effective amount of a compound of formula I. An effective amount to treat or inhibit a viral infection is one of the signs of the viral infection, such as viral lesions, viral load, viral production rate, and mortality, compared to untreated control animals. The amount that would cause the above reduction. The exact amount will vary according to factors known in the art, but at the dose as indicated above for activation of TLR7, or from about 100 ng / kg to about 50 mg / kg, preferably about. A dose of 10 μg / kg to about 5 mg / kg is expected.

In various embodiments, the compound of formula (I) and related formulas are less than about 5 [mu] M, preferably less than about 1 [mu] M, an _{IC 50} for even more preferably binding to TLR7 / 8 less than about 0.100μM Present.

The methods of the invention can be performed either in vitro or in vivo. The susceptibility of a particular cell to treatment with a compound according to the invention can be specifically determined by in-vitro testing, whether in the course of research or in clinical application. Typically, a culture of the cell varies for a period sufficient for the activator to inhibit TLR7 / 8 activity, usually between about 1 hour and 1 week. Combined with compounds according to the invention in concentration. In-vitro treatment can be performed using cultured cells from biopsy samples or cell lines.

The host or patient can also belong to any mammalian species such as primates, specifically humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats and the like. Animal models are the subject of experimental research and provide models for the treatment of human diseases.

Various scientists have developed suitable models or model systems, such as cell culture models and transgenic animal models, for the identification of signaling pathways and for the detection of interactions between various signaling pathways. .. For the determination of certain stages of the signaling cascade, interacting compounds can be utilized to modulate the signal. The compounds according to the invention can also be used as reagents for testing TLR7 / 8 dependent signaling pathways in animal and / or cell culture models or in the clinical disorders referred to in this application.

Moreover, the following teachings herein regarding the use of compounds and derivatives thereof according to formula (I) for the production of pharmaceuticals for prophylactic or therapeutic treatment and / or monitoring are the inhibition of TLR7 / 8 activity. It is considered valid and applicable without limitation to the use of the compounds for.

The present invention also relates to compounds according to formula (I) and / or for prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or transmitted by TLR7 / 8 activity. It also relates to the use of these physiologically acceptable salts. Furthermore, the invention is a formula for the production of a medicament for prophylactic or therapeutic treatment and / or monitoring of a disease caused, mediated, and / or transmitted by TLR7 / 8 activity. With respect to the use of compounds according to (I) and / or physiologically acceptable salts thereof. In some embodiments, the present invention provides the use of a compound according to Formula I or a physiologically acceptable salt thereof for the production of a medicament for the prophylactic or therapeutic treatment of TLR7 / 8 mediated disorders.

The compound of formula (I) and / or a physiologically acceptable salt thereof can also be employed as an intermediate for the preparation of additional pharmaceutically active ingredients. The pharmaceutical preferably comprises, for example, the active ingredient, at least one solid, fluid and / or semi-fluid carrier or excipient, in a non-chemical manner. Optionally, prepared by combining with one or more of other active substances in the appropriate dosage form.

The compound represented by the formula (I) according to the present invention may act as a treatment by being administered once or several times before or after the onset of the disease. The aforementioned compounds and pharmaceuticals for use in the present invention are specifically used for therapeutic treatment. A therapeutically relevant effect is a partial relief of one or more symptoms of the disorder, or one or more physiological or biochemical parameters that are associated with or cause a disease or pathological condition. Return to normal or completely. Monitoring is considered, for example, as a type of treatment, provided that the compounds are administered at distinguishable intervals in order to boost the response and completely eliminate the pathogen and / or symptoms of the disease. Either the same compound or different compounds may be applied. The methods of the invention are also to reduce the likelihood of developing a disorder, or even to prevent the occurrence of a disorder associated with TLR7 / 8 activity in advance, or to treat the symptoms that continue to occur. Can be used.

In the sense of the present invention, prophylactic treatment is for the aforementioned physiological or pathological conditions in which the subject has a familial disposition, genetic defect, or earlier disease. It is wise if you have any of the prerequisites.

The invention further comprises a medicament (including mixtures thereof in all proportions) comprising at least one compound according to the invention and / or pharmaceutically usable derivatives thereof, salts, solvates and stereoisomers thereof. Regarding. In some embodiments, the invention relates to a medicament comprising at least one compound according to the invention and / or a physiologically acceptable salt thereof.

"Medicine" in the meaning of the present invention includes one or more compounds represented by the formula (I) or preparations thereof (eg, pharmaceutical compositions or pharmaceutical preparations), and refers to diseases associated with TLR7 / 8 activity. In the prevention, treatment, follow-up or aftercare of affected patients, a pathogenic modification of their general condition or the condition of a specific area of life can only be established at least temporarily. It is any agent in the medical field that can be used as such.

In various embodiments, the active ingredient may be administered alone or in combination with other treatments. The synergistic effect may be achieved by using more than one compound in the pharmaceutical composition, i.e. the compound of formula (I) is at least one other agent (formula) as the active ingredient. It is combined with either another compound represented by (I) or a compound having a different structure. The active ingredient can be used simultaneously or continuously.

The TLR inhibitors of the present disclosure can be administered in combination with one or more additional therapeutic agents. As described herein, TLR inhibitors can be combined with physiologically acceptable carriers. The methods described herein may be practiced in combination with other therapies that supplement standard therapies for the disorder, such as administration of anti-inflammatory agents.

In some embodiments, the TLR inhibitors as described herein are administered in combination with corticosteroids. In some embodiments, the corticosteroid is a glucocorticosteroid. In some embodiments, the corticosteroid is a mineralocorticoid. Cortisol steroids include cortisolterone and derivatives, their prodrugs, isomers and analogs, cortisone and derivatives, their prodrugs, isomers and analogs (ie, Cortone), aldosterone and derivatives, and their prodrugs. , Isolates and analogs, dexamethasone and derivatives, their prodrugs, isomers and analogs (ie Decadron), prednisone and derivatives, their prodrugs, isomers and analogs (ie Prelone), fludrocortisol And derivatives, their prodrugs, isomers and analogs, hydrocortisones and derivatives, their prodrugs, isomers and analogs (ie, cortisol or Cortef), hydroxycortisone and derivatives, their prodrugs, isomers and analogs. Sodies, betamethasones and derivatives, their prodrugs, isomers and analogs (ie, Celestone), budesonides and derivatives, their prodrugs, isomers and analogs (ie, Entocort EC), methylprednisone and derivatives, theirs. Prodrugs, isomers and analogs (ie, Medrol), prednisone and derivatives, their prodrugs, isomers and analogs (ie, Deltasone, Crtan, Meticorten, Orasone, or Sterapred), triamsinolones and derivatives, their pros Includes, but is not limited to, drugs, isomers and analogs (ie, Kenacort or Kenalog) and the like. In some embodiments, the corticosteroid is a fludrocortisone or derivative, a prodrug, isomer or analog thereof. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, the corticosteroid is a hydroxycortisone or derivative, a prodrug, isomer or analog thereof. In some embodiments, the corticosteroid is hydroxycortisone.

In some embodiments, corticosteroids are approximately 0.001 mg to 1 mg, 0.5 mg to 1 mg, 1 mg to 2 mg, 2 mg to 20 mg, 20 mg to 40 mg, 40 to 80 mg, 80 to 120 mg, 120 mg to 200 mg per day. , 200 mg to 500 mg, or between 500 mg and 1000 mg. In some embodiments, the corticosteroid is about 0.1 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 1 mg / kg, 1 mg / kg to 2 mg / kg, 2 mg / kg to 5 mg per day. / Kg, 5 mg / kg to 10 mg / kg, 10 mg / kg to 15 mg / kg, 15 mg / kg to 20 mg / kg, 20 mg / kg to 25 mg / kg, 25 mg / kg to 35 mg / kg, or 35 mg / kg to 50 mg / kg Administered in any of between kg.

In some embodiments, the TLR inhibitor used in the combination therapy is given in the amount of TLR inhibitor delivered, eg, about 0.1-10 mg / kg, 0.5-10 mg / kg, 1-10 mg. It may be / kg, 0.1 to 20 mg / kg, 0.1 to 20 mg / kg, or 1 to 20 mg / kg.

In some embodiments, the TLR inhibitor is co-administered with one or more additional therapeutic agents, including but not limited to corticosteroids. In some embodiments, the TLR inhibitor is administered sequentially with one or more additional therapeutic agents, including, but not limited to, corticosteroids. In some embodiments, continuous administration is followed by a TLR inhibitor or additional therapeutic agent for either about 1 minute, 5 minutes, 30 minutes, 1 hour, 5 hours, 24 hours, 48 hours, or within a week. Includes administration. In some embodiments, the TLR inhibitor is administered by the same route of administration as the additional therapeutic agent. In some embodiments, the TLR inhibitor is administered by a different dosing route than the additional therapeutic agent. In some embodiments, the additional therapeutic agent is parenteral (eg, central venous line, intraarterial, intravenous, intramuscular, intraperitoneal, intradermal, or subcutaneous injection). It is administered orally, gastrointestinal, topically, nasopharynx, and transpulmonary (eg, by inhalation or intranasal). In some embodiments, an additional therapeutic agent is a corticosteroid.

The disclosed compounds represented by formula I can be administered in combination with other known therapeutic agents, including anti-cancer agents. As used herein, the term "antineoplastic agent" refers to any agent given to a patient with cancer for the purpose of treating cancer.

The anti-cancer treatments defined above may be applied as monotherapy or in addition to the compounds represented by formula I disclosed herein, conventional surgery or radiotherapy or medicine. May be accompanied by therapy). Such drug treatments (eg, chemotherapy or targeted treatment) include one or more of the following antitumor agents, preferably one of them:
Alkylating agents: altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitractor, nimustin, lanimustine, temozolomide , Thiotepa, temozolomide, chlormethine, carbocon; apadicon, hotemustine, gluphosfamide, pariphosphamide, pipobroman, trophosphamide, uramstine, TH-302 ⁴ , VAL-083 ^4, etc.;
Platinum compounds: carboplatin, cisplatin, eptaplatin, milliplatin hydrate, oxaliplatin, lovaplatin, nedaplatin, picoplatin, satraplatin; robaplatin, nedaplatin, picoplatin, satraplatin, etc.;
DNA modifiers: amrubicin, bisantren, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amrubicin, brostaricin, pixantron, laromstin ^1,3, etc.;
Topoisomerase inhibitors: etoposide, irinotecan, razoxane, sobzoxane, teniposide, topotecan; amonafide, verotecan, elliptinium acetate, boleroxin, etc.;
Microtubule modifiers: cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, binplastine, vincristine, vinorelbine, vindesine, vinflunin; phosbretabulin, tesetaxel, etc .;
Anti-metabolites: asparaginase ³ , azacitidine, levofolinate calcium, capecitabine, cladribine, cytarabine, enocitabine, floxuridin, fludarabin, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nerarabine, pemetrexed, pralatrexed , Erasitabin, Larchitrexed, Sepacitabin, Tegafur ^2,3 , Trimethotrexate, etc .;
Anticancer antibiotics: bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, stereptozocin, valrubicin, diostatin, sorbicin, daunorubicin, plicamycin; acralubicin, pepromycin, pyrarubicin, etc.
Hormones / antagonists: avalerix, avilateron, bicalutamide, busererin, carsterone, chlorotonianicene, degalerix, dexamethasone, estradiol, fulvestrant, fluoroximesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megesterol , Mitotan, nafarelin, nandrolone, niltamide, octreotide, prednisolone, laroxifen, tamoxifen, silotropin alpha, tremiphen, trilostane, tryptrelin, diethylstilbestrol; acorbifen, dannazole, deslorerin, epithiostanol, orteronel, enzalutamide ^1,3, etc.
Aromatase inhibitors: aminoglutethimide, anastrozole, exemestane, fadrosole, letrozole, test lactone; formestane, etc.;
Small molecule kinase inhibitors: crizotinib, dasatinib, errotinib, imatinib, lapatinib, nilotinib, pazopanib, legorafenib, luxolitinib, sorafenib, snitinib, bandetanib, vemurafenib, bostinib, gefitinib, bostinib, gefitinib Sutaurin, nintedanib, lenvatinib, Rinifanibu, Rinshichinibu, Mashichinibu, midostaurin, motesanib, neratinib, Oranchinibu, perifosine, Ponachinibu, Radochinibu, Rigosachibu, tipifarnib, Chibanchinibu, Chibozanibu, Trametinib, Pimaseruchibu, yellowtail Banibu alaninate diisocyanate, cediranib, Apachinibu ^4, Kabozanchinibu S- malate ^1,3, Iburuchinibu ^1,3, Ikochinibu ^4, Buparurishibu ^2, Shipachinibu (cipatinib) ^4, cobimetinib ^1,3, Iderarishibu ^1,3, etc. Fedorachinibu ^1, XL-647 ^4;
Photosensitizer: Methoxsalen ³ ; Polyphymer sodium, Talaporfin, Temoporfin, etc.;
Antibodies: alemtuzumab, Beshiresomabu, brentuximab Bedochin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab ^2,3; Katsumakisomabu, Erotsuzumabu, epratuzumab, Faretsuzumabu, mogamulizumab, Neshitsumumabu, nimotuzumab, Obinutsuzumabu, Okaratsuzumabu, oregovomab, Ramucirumab, Rirotsumumabu, Shirutsukishimabu, tocilizumab, zalutumumab, zanolimumab, matuzumab, Darotsuzumabu ^1,2,3, Onarutsuzumabu ^1,3, Rakotsumomabu (racotumomab) ^1, Tabarumabu ^1,3, EMD-525 797 ^4, nivolumab ^1,3 Such;
Cytokines: aldes leukin, interferon alpha ² , interferon alpha 2a ³ , interferon alpha 2b ^2,3 ; selmoleukin, tasonermin, teseroykin, operelbekin ^1,3 , recombinant interferon beta-1a ^4, etc.;
Drug Conjugates: Deniroykin difchitox, Ibritumomab Chiuxetan, Iobenguane I123, Prednimustin, Trastuzumab Emtancin, Estramstin, Gemtuzumab, Ozogamycin, Aflibercept, Ozogamycin, Aflibercept, Ozogamycin, Aflibercept Monatox, technitium (99mTc) alcitsumomab ^1,3 , bintafolide ^1,3, etc .;
Vaccines: Cyprucel ³ ; Vitespene ³ , Emepepimut-S ³ , oncoVAX ⁴ , Lindpepimut ³ , TroVax ⁴ , MGN-1601 ⁴ , MGN-1703 ^4, etc .;
Others: aritretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imikimod, lenalidomide, lentinan, methyrosine, mifamultide, pamidronic acid, pegaspargase, pentostatin, cyprucel ³ , sizophyllan, tamibarotene, temsirolimus, temsirolimus Acid, bortezomib; celecoxib, sirentide, entinostat, ethanidazole, ganetespib, idronoxyl, iniparib, ixazomib, ronidamine, nimorazole, parabinostat, peretinoin, pentidepsin, pomalidomide, procodazole, protodazole (procodazol) , simultaneous file Singh, tirapazamine, Tosedosutatto, Torabederusen, ubenimex, valspodar, Gendicine ^4, picibanil ^4, Reoraishin ^4, lettuce pin mycin hydrochloride ^1,3, Torebananibu ^2,3, Birirujin ^4, carfilzomib ^1,3, endostatin ^4, Imunokoteru (immucothel) ⁴ , Verinostat ³ , MGN-1703 ⁴ .
( ¹ Prop. INN (Proposed International Nonproprietary Name); ² Rec. INN (Recommended International Nonproprietary Name); ³ USAN (US Adopted Name); ⁴ No INN).

In some embodiments, the combination of the TLR inhibitor and one or more additional therapeutic agents achieves the same results as compared to the effective dose administered when the TLR inhibitor or additional therapeutic agent is administered alone. Effective amount of TLR inhibitor and / or one or more additional therapeutic agents administered to be administered (dosage volume, dosage concentration, and / or total drug dose). , But not limited to). In some embodiments, the combination of a TLR inhibitor and a corticosteroid reduces the effective amount of the corticosteroid administered as compared to the corticosteroid administered alone. In some embodiments, the combination of a TLR inhibitor and an additional therapeutic agent reduces the frequency of therapeutic agent administration as compared to the administration of the additional therapeutic agent alone. In some embodiments, the combination of a TLR inhibitor with an additional therapeutic agent reduces the total duration of treatment compared to administration of the additional therapeutic agent alone. In some embodiments, the combination of a TLR inhibitor with an additional therapeutic agent reduces the side effects associated with the administration of the additional therapeutic agent alone. In some embodiments, an additional therapeutic agent is a corticosteroid. In some embodiments, the corticosteroid is a fludrocortisone or derivative, a prodrug, isomer or analog thereof. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, the combination of an effective amount of TLR inhibitor and additional therapeutic agent is more efficient as compared to an effective amount of TLR inhibitor or additional therapeutic agent alone.

TLR inhibitors are also any material that modulates either a humoral and / or cell-mediated immune response (eg, a raw viral, bacterial, or parasitic immunogen; of an inactivating virus. Tumor-derived, protozoan, living organism-derived, fungal or bacterial immunogens, toxoids, toxins; self-antigens; polysaccharides; proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines; It may also be useful as a vaccine adjuvant for use in combination with recombinant proteins; glycoproteins; peptides; etc.). In some aspects, combination therapies, including but not limited to combinations of TLR inhibitors and vaccines, are used in the treatment of autoimmune diseases or inflammatory disorders. In some aspects, combination therapies, including but not limited to combinations of TLR inhibitors and vaccines, are used in the treatment of infectious diseases.

In some embodiments, combination therapies, including but not limited to combinations of TLR inhibitors and corticosteroids, are used in the treatment of autoimmune diseases or inflammatory disorders. In some embodiments, the autoimmune disease is selected from rheumatoid arthritis, systemic lupus erythematosus, autoimmune skin disease, multiple sclerosis, pancreatitis, glomerulonephritis, pyelonephritis, sclerosing cholangitis, and type I diabetes. Is not limited to these. In some embodiments, the autoimmune disease is Sjogren's disease.

Also provided herein are kits containing TLR inhibitors as provided herein, and instructions for use in methods that inhibit TLR7 and / or TLR8 dependent immune responses. ..

The kit may include a TLR inhibitor (or formulation containing a TLR inhibitor) as described herein, and one or more containers containing a set of instructions, generally written instructions, but the intended procedure (eg, as an example). Suppression of response to TLR7 and / or TLR8 agonists, suppression of TLR7 and / or TLR8-dependent immune response, recovery of one or more symptoms of autoimmune disease, recovery of symptoms of chronic inflammatory disease, resistance to viruses Use and dosage of TLR inhibitors or formulations for reducing cytokine production in the response and / or treating and / or preventing one or more symptoms of a disease or disorder mediated by TLR7 and / or TLR8. An electronic storage medium (eg, a magnetic diskette or optical disk) containing instructions regarding the above may also be acceptable. The instructions included in the kit generally include information about the dosage, dosing schedule, and route of dosing for the intended treatment. Containers for TLR inhibitors (or formulations containing TLR inhibitors) may be unit doses, bulk packages (eg, multi-dose packages) or sub-unit doses. The kit may further include a container containing the adjuvant.

In another aspect, the invention comprises effective amounts of compounds according to the invention and / or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof (including mixtures thereof in any ratio). , And optionally, a kit consisting of separate packs of effective amounts of additional active ingredients. The kit includes suitable containers such as boxes, individual bottles, bags or ampoules. The kit may include, for example, separate ampoules, each containing effective amounts of the compounds according to the invention and / or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof. (Including their mixtures in proportion), and optionally, an effective amount of additional active ingredient is contained in dissolved or lyophilized form.

As used herein, the terms "treatment," "treating," and "treating" mean stopping the onset of a disease or disorder, or one or more of its symptoms, as described herein. Reversing, mitigating, delaying, or inhibiting their progression. In some embodiments, the treatment is given after the onset of one or more symptoms. In other embodiments, the treatment is given in the absence of symptoms. For example, treatment is given to susceptible individuals prior to the onset of symptoms (eg, in the light of the history of the condition and / or in the light of genetic or other susceptibility factors). Treatment also continues after the symptoms have resolved, eg, to prevent or delay their recurrence.

Compounds and compositions are administered using any amount and any route of administration that, according to the methods of the invention, are effective in treating or reducing the severity of the disorders provided above. Will be done. The exact amount required will vary from subject to subject, depending on the subject's species, age, and overall condition, severity of infection, specific agent, mode of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form due to ease of administration and uniformity of dosage. As used herein, the expression "dosage unit form" refers to a physically individual unit of agent appropriate for the patient to be treated. However, it will be understood that the total daily use of the compounds and compositions of the present invention will be determined by the attending physician within reasonable medical judgment. The specific dose levels that are effective for any particular patient or organism are the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific compound employed; the age, weight of the patient, Overall health, gender and diet; time of administration, route of administration, and rate of excretion of the specific compound adopted; duration of treatment; drug used in combination with or concurrently with the specific compound adopted, and It will depend on a variety of factors, including similar factors well known in medicine.

The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals, orally, transrectally, parenterally, in large cisterns, intravaginally, intraperitoneally. Can be administered topically (as by powder, ointment, or drops) orally, as an oral spray or nasal spray or the like, depending on the severity of the infection being treated. .. In some embodiments, the compounds of the present invention have a body weight of about 0.01 mg / kg (subject) to about 100 mg / kg, preferably about 1 mg / kg body weight (subject) per day in order to obtain the desired therapeutic effect. Administered orally or parenterally at least once daily at dosage levels from to about 50 mg / kg.

In some embodiments, a therapeutically effective amount of the compound represented by formula (I) and related formulas and other active ingredients in such amounts are, for example, the age and weight of the animal, the exact disease state requiring treatment It depends on a number of factors, including and its severity, the nature of the formulation, and the method of administration, and is ultimately determined by the treating physician or veterinarian. However, effective amounts of compounds generally range from 0.1 to 100 mg / kg body weight (of the recipient (mammal)) per day, specifically typically 1 to 10 mg / kg per day. It is in the range up to kg weight. Thus, the actual daily dose of an adult mammal weighing 70 kg is typically between 70 mg and 700 mg, where this amount can be administered as an individual dose per day or Usually, a set of partial doses (eg, 2, 3, 4, 5, 6, etc.) can be administered per day so that the total daily dose is the same. An effective amount of salt or solvate or an effective amount of its physiologically functional derivative can be determined as a fraction of the effective amount of the compound itself.

In some embodiments, the pharmaceutical formulation may be administered in the form of a dosage unit, comprising a predetermined amount of the active ingredient per dosage unit. Such units depend on, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, specifically preferably 5 mg to 100 mg, depending on the condition of the disease being treated, the method of administration, and the age, weight and condition of the patient. Can comprise a compound according to the invention, or the pharmaceutical formulation can be administered in the form of a dosage unit containing a predetermined amount of active ingredient per dosage unit. A preferred dosage unit formulation is a formulation containing a daily dose or partial dose or the corresponding fraction of the active ingredient as indicated above. Furthermore, this type of pharmaceutical formulation can be prepared using processes commonly known in the pharmaceutical art.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form is optionally an inert diluent commonly used in the art, such as water or other solvent, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, Benzyl alcohol, benzyl benzoic acid, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, Contains solubilizers and emulsifiers such as fatty acid esters of polyethylene glycol and sorbitan, and mixtures thereof. In addition to the Inactive Diluent, the oral composition also includes adjuvants such as wetting agents, emulsifying agents and suspending agents, sweeteners, flavoring agents, and coloring agents.

Injectable preparations, such as sterile injectable aqueous or greasy suspensions, are formulated according to known techniques (art) using suitable dispersants or wetting agents and suspending agents. Will be done. Sterilized injectable preparations are also sterile injectable solutions, suspensions or emulsions in non-toxic parenteral acceptable diluents or solvents, eg, solutions in 1,3-butanediol. As. Of the acceptable vehicles and solvents that may be employed, water, Ringer's solution, U.S.P. and isotonic sodium chloride solutions. In addition, sterile fixed oils have traditionally been employed as solvents or suspension media. For this purpose, any bland fixing oil that can be employed includes synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in injectable preparations.

Injectable formulations are, for example, sterile solids that can be dissolved or dispersed in sterile water or other sterile injectable medium, either by filtration through a bacterial-retaining filter or prior to use. It can be sterilized by incorporating a sterilizing agent in the form of a composition.

It is often desired to delay the absorption of the compounds from subcutaneous or intramuscular injections in order to prolong the effects of the compounds of the invention. This is achieved by the use of liquid suspensions of sparingly soluble crystalline or amorphous materials. The rate of absorption of a compound then depends on its rate of dissolution, which in the same way can depend on crystal size and crystal morphology. Alternatively, delayed absorption of the compound form administered parenterally is also achieved by dissolving or suspending the compound in an oil vehicle. The injectable depot form is made by forming a microencapsulated matrix of compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of compound release can be controlled depending on the compound-to-polymer ratio and the properties of the specific polymer used. Examples of other biodegradable polymers include poly (orthoester) and poly (anhydrous). Injectable depot formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with living tissue.

Compositions for transrectal or vaginal administration are preferably prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers (cocoa butter, polyethylene glycol, etc.). A suppository to obtain, or a suppository wax that melts in the rectum or vaginal cavity to release the active compound where it is solid at ambient temperature but liquid at body temperature.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is at least one pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) starch, lactose, sucrose, glucose, mannitol, And fillers or bulking agents such as silicic acid, b) binders such as carboxymethyl cellulose, alginic acid, gelatin, polyvinylpyrrolidinone, sucrose, and acacia rubber, c) water retention agents such as glycerol, d) agar, calcium carbonate, Disintegrants such as potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds. , G) Wetting agents such as cetyl alcohol and glycerol monostearate, h) Absorbents such as kaolin and bentonite clay, and i) Lubricating talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and the like. It is mixed with the agent, as well as a mixture of these. In the case of capsules, tablets and pills, the dosage form also optionally includes a buffer.

Similar types of solid compositions are also employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation technology. They may also optionally contain opalescent agents and may also be compositions in which they release only the active ingredient (s) or preferentially, in some part of the intestinal tract, in an optional delayed manner. Examples of embedding compositions that can be used include polymer substances and waxes. Similar types of solid compositions are also employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycol.

The active compound can also be in microencapsulated form with one or more excipients as noted above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release control coatings and other coatings well known in the pharmaceutical formulation technology. In such a solid dosage form, the active compound may be miscible with at least one inert diluent such as sucrose, lactose or starch. The usual dosage forms also include additional substances other than the Inactive Diluent, such as tableting lubricants such as magnesium stearate and microcrystalline cellulose and other tablet aids (aids). In the case of capsules, tablets and pills, the dosage form also optionally includes a buffer. They may also optionally contain opalescent agents and may also be compositions in which they release only the active ingredient (s) or preferentially, in some part of the intestinal tract, in an optional delayed manner. Examples of embedding compositions that can be used include polymeric substances and polymeric waxes.

Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservative or required buffer. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the present invention. In addition, the present invention contemplates the use of percutaneous patches with the additional advantage of providing controlled delivery of compounds to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of compounds across the skin. Its rate can be controlled either by providing a rate control membrane or by dispersing the compound in a polymer matrix or gel.

According to one aspect, the present invention relates to a method of inhibiting TLR7 / 8 activity in a biological sample, wherein the method comprises contacting the biological sample with a compound of the invention or a composition containing the compound.

According to another aspect, the present invention relates to a method of inhibiting TLR7 / 8 or a mutant thereof, activity in a biological sample in an aggressive manner, wherein the method comprises the biological sample as a compound of the invention or a compound thereof. Includes the step of contacting the composition comprising.

The compounds of the present invention are unique tools for understanding the biological role of TLR7 / 8 (when affecting and being influenced by TLR7 / 8 production and TLR7 / 8 interactions). It is useful in-vitro as (including assessment of a number of possible factors). This compound is also useful for the development of other compounds that interact with TLR7 / 8. This is because the compounds provide important structure-activity relationship (SAR) information that facilitates their development. The compound of the present invention that binds to TLR7 / 8 is used as a reagent for detecting TLR7 / 8 from living cells, fixed cells, biological fluids, tissue homogenates, purified natural biomaterials, and the like. obtain. For example, cells expressing TLR7 / 8 can be identified by labeling such compounds. In addition, based on their ability to bind to TLR7 / 8, the compounds of the invention include in-situ staining, FACS (fluorescence activated cell sorting), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), ELISA (. It can be used in enzyme-linked immunosorbent assay), etc., or in purifying cells expressing TLR7 / 8 inside permeable cells. The compounds of the present invention can also be utilized as commercial research reagents for a variety of medical research and diagnostic uses. Such use is as follows: Use as a calibration standard for quantifying the activity of TLR7 / 8 candidate inhibitors in various functional assays; blocking reagents in random screening of compounds, i.e. in searching for new families of TLR7 / 8 ligands. As used, the compound can be used to block the recovery of the currently claimed TLR7 / 8 compound; its use in co-crystals with TLR7 / 8, ie the compounds of the invention bind to TLR7 / 8. By forming crystals of the compound in the compound, X-ray crystal structure analysis will allow determination of the structure of the enzyme / compound; other studies and diagnostic applications, where TLR7 / 8 is preferably active. The conjugation or such activation is conveniently calibrated for known amounts of TLR7 / 8 inhibitors and the like; use in assays as probes to determine expression of TLR7 / 8 in cells; Includes, but is not limited to, developing an assay for detecting a compound that binds to the same site as the TLR7 / 8 binding ligand.

The compounds of the present invention may be applied either on their own and / or in combination with anthropometric measurements for the diagnosis of treatment efficacy. Pharmaceutical compositions containing the compound and the use of the compound to treat conditions mediated by TLR7 / 8 cause a direct and immediate improvement in the state of health, whether human or animal. It is a promising new approach to a wide range of treatments. The new chemical entities of the present invention, which are orally bioavailables and are active, improve patient convenience and physician compliance.

The compounds represented by the formula (I), their salts, isomers, tautomers, enantiomer morphologies, diastereomers, racemic compounds, derivatives, prodrugs and / or metabolites have high specificity and It is characterized by stability, low manufacturing costs, and convenient handleability. These features are the basis for a reproducible action, which includes the lack of cross-reactivity, and a reliable and safe interaction with the target structure. It forms the basis for.

The term "biological sample" as used herein, without limitation, cell cultures or extracts thereof; biopsy materials obtained from mammals or extracts thereof; and blood, saliva, and the like. Includes urine, feces, semen, tears, or other body fluids, or extracts thereof.

Modulation of TLR7 / 8, or a mutant thereof, activity in a biological sample is useful for a variety of purposes known to those of skill in the art. Examples of such objectives include, but are not limited to, blood transfusions, organ transplants, biological specimen storage, and bioassays.

Illustrative In certain exemplary embodiments, compounds are prepared according to the following general procedures, as depicted in the examples below. Although general methods describe the synthesis of certain compounds of the invention, the following general methods and other methods known to those of skill in the art also include all compounds as described herein, and of these compounds. It will be appreciated that it can be applied to each subclass and species.

The symbols and conventions used in the processes, schemes, and examples described below are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry.

Unless otherwise indicated, all temperatures are expressed in degrees Celsius.

All solvents used are commercially available and used without further purification. The reaction was typically carried out using an anhydrous solvent under the inert atmosphere of nitrogen. Flash column chromatography was generally performed using Silica gel 60 (0.035-0.070 mm particle size).

All NMR experiments can be performed on a Bruker Mercury Plus 400 NMR spectroscopy with a Bruker 400BBFO probe at 400MHz for proton NMR, or on a Bruker Mercury Plus 300 NMR spectrometer with a Bruker 300BBFO probe at 300MHz for proton NMR. Recorded on one of the Bruker Avance III 400 NMR spectroscopy with a Bruker PABBO BB-1H / D Z GRD probe at 400 MHz for NMR. All deuterated solvents typically contained 0.03% to 0.05% v / v of tetramethylsilane, which was used as a reference signal (both ¹ H and ¹³ C set to d 0.00). When the deuterated solvent did not contain tetramethylsilane, the peaks of the remaining non-deuterated solvent were set according to published guidelines (J. Org. Chem., Vol. 62, No. 21, 1997). , Used as a reference signal.

LC-MS analysis was performed on one of the following two instruments:

LC-MS analysis was performed on a SHIMADZU LC-MS instrument consisting of a UFLC 20-AD system and an LCMS 2020 MS detector. The columns used were Shim-pack XR-ODS, 2.2 μm, 3.0 × 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in acetonitrile) over 2.2 minutes. The total run time was 3.6 minutes. The column temperature was 40 ° C. and the flow rate was 1.0 mL / min. The Diode Array detector was scanned at 200-400 nm. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive or negative mode. The mass spectrometer scanned between m / z 90 and 900 with a scan time of 0.6 s.

Agilent 1200 Series Mass Spectrometer from Agilent Technologies using either atmospheric pressure chemical ionization (APCI) or electrospray ionization (ESI). The diode array detector was scanned at 200-400 nm. The mass spectrometer was scanned between m / z 90-900 with a scan time of 0.6 seconds. Column: XBridge C8, 3.5 μm, 4.6 x 50 mm; Solvent A: Water + 0.1% TFA; Solvent B: ACN + 0.1% TFA; Flow velocity (Flow): 2 ml / min; Gradient: 0 min: 5% B, 8 min : 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min 5% B or LC / MS WatersZMD (ESI).

HPLC data can be obtained from a SHIMAZU LC-MS instrument or column (XBridge C8, 3.5 μm, 4.6x50 mm) and two mobile phases (mobile phase A: water + 0.1% TFA; mobile phase B: ACN + 0.1). % TFA) was either used by Agilent 1100 series HPLC from Agilent technologies. The flow velocity is 2 ml / min. Gradient methods are: 0 min: 5% B; 8 min: 100% B; 8.1 min: 100% B; 8.5 min: 5% B; 10 min 5% B unless otherwise suggested.

In general, compounds according to formula (I) and related formulas of the present invention can be prepared from readily available starting materials. If such starting materials are not commercially available, they may be prepared by standard synthetic techniques. In general, the synthetic pathway for any of the individual compounds represented by formula (I) and related formulas will depend on the particular substituent of each molecule. Such factors will be understood by those skilled in the art. The following general methods and procedures described below in the examples may be employed to prepare compounds represented by formula (I) and related formulas. The reaction conditions depicted in the following schemes, such as temperature, solvent, or co-reagents, are given by way of example only and are not limited. Given typical or preferred experimental conditions (ie, reaction temperature, time, moles of reagents, solvent, etc.), it is understood that other experimental conditions may also be used unless so stated. Will. Optimal reaction conditions may vary with the specific reagents or solvents used, but such conditions can be determined by one of ordinary skill in the art using routine optimization procedures. For all methods of protection and deprotection, see Philip J. Kocienski, in “Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and Theodora W. Greene and Peter GM Wuts in “Protective Groups in Organic Synthesis”, see Wiley Interscience, ³ rd Edition 1999.
Intermediate 1: 8-bromoquinoxaline-5-carbonitrile

5-Bromo-8-methylquinoxaline: 1-bromopyrrolidone-2,5-dione (27.0 g, 151.7 mmol) in a solution of 5-methylquinoxaline (9.50 g, 66.0 mmol) in acetonitrile (80 mL). Was added at room temperature. The resulting solution was stirred at 60 ° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (500 mL). The insoluble solids in the mixture were filtered off and the filtrate was washed with brine and dried over Na ₂ SO ₄ . Removal of the solvent under reduced pressure produced 5-bromo-8-methylquinoxaline as a brown solid (6.00 g, 41%). MS: m / z = 222.9 [M + H] ⁺ .

5-Bromo-8- (dibromomethyl) quinoxaline: To a solution of 5-bromo-8-methylquinoxaline (6.00 g, 27.0 mmol) in CCl ₄ (200 mL), NBS (19.2 g, 108.1 mmol) and AIBN (0.71 g, 4.3 mmol) was added at room temperature. The resulting solution was then stirred at 80 ° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (500 mL). The insoluble solids in the mixture were filtered off, then the filtrate was washed with brine and dried over Na ₂ SO ₄ . 5-Bromo-8- (dibromomethyl) quinoxaline is a pale yellow solid by removing the solvent under reduced pressure and purifying the residue by flash chromatography eluting with EtOAc (0% -5% gradient) in petroleum ether. It was produced as (7.15 g, 70%). MS: m / z = 378.7 [M + H] ⁺ .

8-Bromoquinoxaline-5-carbaldehyde: AgNO ₃ (24.3 g) in water (90 mL) into a solution of 5-bromo-8- (dibromomethyl) quinoxaline (13.5 g, 35.7 mmol) in ethanol (290 mL). , 142.9 mmol) was added dropwise at room temperature. The resulting mixture was then stirred at room temperature for 1 h. When the reaction was complete, the reaction mixture was diluted with acetonitrile (300 mL) and precipitation occurred. The precipitate was filtered off and the filtrate was concentrated under reduced pressure to produce 8-bromoquinoxaline-5-carbaldehyde as a yellow solid (10.0 g, crude). MS: m / z = 236.8 [M + H] ⁺ .

(E) -8-Bromoquinoxaline-5-carbaldehyde: In a solution of 8-bromoquinoxaline-5-carbaldehyde (10 g, crude) in ethanol (100 mL), NaOAc (6.34 g, 73.4 mmol) and NH ₂ OH · HCl (3.12 g, 42.7 mmol) was added at room temperature. The resulting mixture was stirred at 70 ° C. for 3 hours. When the reaction was complete, the insoluble solids in the reaction mixture were filtered off at 70 ° C. and then the filtrate was cooled to 0 ° C. to cause precipitation. By collecting the precipitate by filtration and drying it in the oven, (E) -N-[(8-bromoquinoxaline-5-yl) methylidene] hydroxylamine was a yellow solid (2.96 g, 33 in 2 steps). %) Was produced. MS: m / z = 253.9 [M + H] ⁺ .

8-Bromoquinoxaline-5-Carbonitrile: Cu to a solution of (E) -N-[(8-bromoquinoxaline-5-yl) methylidene] hydroxylamine (3.47 g, 13.8 mmol) in acetonitrile (20 mL). (OAc) ₂ (577 mg, 3.18 mmol) and acetic acid (1.24 g, 20.7 mmol) were added at room temperature. The resulting mixture was stirred at 88 ° C. for 15 hours. After cooling to room temperature, the reaction mixture was diluted with acetonitrile (10 mL). The insoluble solid in the mixture was filtered off and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography eluting with EtOAc (0% -5% gradient) in petroleum ether produces 8-bromoquinoxaline-5-carbonitrile as a yellow solid (1.22 g, 38%). It was. MS: m / z = 235.8 [M + H] ⁺ .
Intermediate 2: 5-bromo-8-methyl- [1,7] diazanaphthalene

5-Bromo-8-methyl- [1,7] naphthylene: 5-bromo-2-methyl-pyridine-3-ylamine (3.00 g; 16.0 mmo), glycerol (4.7 mL; 64.1 mmol), sulfuric acid Sulfuric acid (5.6 mL; 96.2 mmol) was added dropwise to a mixture of iron (ii) heptahydrate (892 mg; 3.2 mmol). The resulting mixture was heated at 120 ° C. overnight. The reaction mixture was treated with ice, 2N sodium hydroxide solution, ethyl acetate and dichloromethane. After filtering to remove the dark brown solid, the organic layer was separated, washed with brine, dried and concentrated. The crude product was purified by chromatography on silica gel eluting with ethyl acetate and hexanes to give 5-bromo-8-methyl- [1,7] naphthylene (470 mg, 13%). MS: m / z = 224 [M + H] ⁺ .
Intermediate 3: 8-chloropyrido [2,3-b] pyrazine

8-Chloropyrido [2,3-b] pyrazine: 4-chloropyridin-2,3-diamine (1.90 g, 13.20 mmol) in THF (100 mL) solution with oxadiazole (1.00 g, 17.20 mmol) Was added at room temperature. Then, the resulting solution was stirred at room temperature for 6 hours. .. When the reaction is complete, the reaction mixture is concentrated under reduced pressure and the residue is purified by flash chromatography eluting with EtOAc (0% -50% gradient) in petroleum ether to give 8-chloropyrazine [2,3]. -B] Pyrazine was produced as a yellow solid (2.10 g, 91%). MS: m / z = 166.1 [M + H] ⁺ .
Intermediate 4: 4-bromo-1,2-dimethyl-1H-pyrrolo [2,3-b] pyridine

4-Bromo-1,2-dimethyl-1H-pyrrolo [2,3-b] pyridine: 0 ^o C, 4-bromo-2-methyl-1H-pyrrolo [2,3-b] pyridine (6.00 g) , 27.0 mmol) to a solution of N, N-dimethylformamide (60 mL) was added sodium hydride (1.62 g, 40.5 mmol). The reaction was stirred at 0 ^o C for 15 minutes, then iodomethane (2.1 mL, 32.4 mmol) was added and the resulting mixture was stirred at room temperature for 8 h. When the reaction was complete, the reaction mixture was terminated with water (250 mL) and the resulting mixture was extracted with ethyl acetate (3x100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The gum-like substance of the residue was powdered with hexane (40 mL) and dried, and 4-bromo-1,2-dimethyl-1H-pyrrolo [2,3-b] pyridine was a brown semi-solid (3.80 g). , 62%). MS: m / z = 227 [M + H] ⁺ .
Example 1: Synthesis of compound 1 (8-[(3R, 4R) -3-amino-4-methylpyrrolidine-1-yl] quinoxaline-5-carbonitrile)

tert-Butyl N-[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl) -4-methylpyrrolidin-3-yl] Carbamate: 8-bromoquinoxaline-5-carbonitrile (900 mg, 3. DIEA (1.58 g) in a solution of tert-butyl N-[(3R, 4R) -4-methylpyrrolidin-3-yl] carbamate (808 mg, 4.03 mmol) in N, N-dimethylformamide (7 mL). , 12.20 mmol) was added at room temperature. The reaction solution was stirred at 130 ^o C for 3 hours. When the reaction was completed, it was stopped by the addition of water (30 mL). The resulting mixture was extracted with ethyl acetate (50 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and tert-butyl N-[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl) -4-methylpyrrolidine-3-yl] carbamate was a yellow solid (1.19 g, 44). %) Produced as. MS: m / z = 354.1 [M + H] ⁺ .

8-[(3R, 4R) -3-amino-4-methylpyrrolidine-1-yl] quinoxaline-5: tert-butyl N-[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl] ) -4-Methylpyrrolidine-3-yl] A hydrochloric acid solution (12N, 6 mL, 72 mmol) was added to a MeOH solution of carbamate (720 mg, 2.04 mmol) at room temperature. The resulting mixture was stirred at room temperature for 6 hours. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBride Prep C18 OBD column, 250 mm, 5 um, 13 nm; mobile phase, acetonitrile in water (0). (Contains 0.05% NH ₃ .H ₂ O), 29% -42% gradient at 8 min; detector, UV 254 nm. 8-[(3R, 4R) -3-amino-4-methylpyrrolidine-1-yl] quinoxaline-5-carbonitrile was obtained as a white solid (490 mg, 95%).

Compound 1: HPLC: 98.1% purity, RT = 1.05 min. MS: m / z = 254.3 [M + H] ⁺ . ¹ H NMR (400 MHz, methanol-d _4, ppm) δ 8.79 (d, J = 1.8 Hz, 1 H), 8.73 (d, J = 1.8 Hz, 1 H), 7.97-7.89 (m, 1 H) , 6.72 (d, J = 8.8 Hz, 1 H), 4.21-4.12 (m, 1 H), 4.05-3.95 (m, 1 H), 3.93-3.85 (m, 1 H), 3.79-3.69 (m, 1 H), 3.63-3.52 (m, 1 H), 2.53-2.38 (m, 1 H), 1.16 (d, J = 7.0 Hz, 3 H).

The following compounds were synthesized in a similar manner:

Compounds 568- (3-amino-4-methyl-pyrrolidin-1-yl) -quinoxalin-5-carbonitrile hydrochloride: 8-bromoquinoxalin-5-carbonitrile and (4-methyl-pyrrolidin-3-yl) -From carbamic acid tert-butyl ester. HPLC: 92% purity, RT = 1.50 min. MS: m / z = 254 [M + H] ⁺ .
Example 2: Compound 2 (N-[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl) -4-methylpyrrolidine-3-yl] -2- (1-methylpiperidin-4-yl) Synthesis of acetamide)

N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] -2- (1-methylpiperidin-4-yl) acetamide: 8-[( 3R, 4R) -3-amino-4-methylpyrrolidine-1-yl] quinoxaline-5-carbonitrile (48 mg, 0.19 mmol) in N, N-dimethylformamide (10 mL) solution in 2- (1-methyl Piperidine-4-yl) acetic acid (59 mg, 0.38 mmol), DIEA (145 mg, 1.13 mmol) and HATU (143 mg, 0.38 mmol) were added at room temperature. The resulting solution was stirred at room temperature for 14 hours. When the reaction was complete, the solvent was removed under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBride Shield RP18 OBD column, 150 mm, 5 um, 13 nm; mobile phase, acetonitrile in water (10 mM NH ₄ HCO _3). Contains), 13% -40% gradient at 8 min; detector, UV 254 nm. N-[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl) -4-methylpyrrolidine-3-yl] -2- (1-methylpiperidin-4-yl) acetamide as a yellow solid (18 mg) , 25%).

Compound 2: HPLC: 92.4% purity, RT = 3.85 min. MS: m / z = 393.4 [M + H] ⁺ . ¹ H NMR (400 MHz, methanol-d _4, ppm) δ 8.81 (d, J = 1.8 Hz, 1 H), 8.75 (d, J = 1.8 Hz, 1 H), 7.95 (d, J = 8.7 Hz, 1 H), 6.75 (d, J = 8.7 Hz, 1 H), 4.64-4.56 (m, 1 H), 4.31-4.21 (m, 1 H), 4.08-3.92 (m, 2 H), 3.74-3.64 (m, 1 H), 2.89-2.78 (m, 2 H), 2.69-2.54 (m, 1 H), 2.29-2.09 (m, 5 H), 2.06-1.94 (m, 2 H), 1.83-1.62 (m, 3 H), 1.37-1.20 (m, 2 H), 1.10 (d, J = 6.8 Hz, 3 H).

The following compounds were synthesized in a similar manner:

Compound 7 (N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] -2- (morpholine-4-yl) acetamide): 8-[ Purified from (3R, 4R) -3-amino-4-methylpyrrolidine-1-yl] quinoxalin-5-carbonitrile and 2- (morpholine-4-yl) acetamide by prep-HPLC under the following conditions: Column, XBridge Compound C18 OBD column, 150 mm, 5 um, 13 nm; mobile phase, acetonitrile in water (containing 10 mM NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 5% to 75% gradient at 7 min; detection Vessel, UV 254 nm (18 mg, 25%, yellow solid). HPLC: 91.7% purity, RT = 2.14 min. MS: m / z = 381.3 [M + H] ⁺ . ¹ H NMR (400 MHz, methanol-d _4, ppm) δ 8.83 (d, J = 1.8 Hz, 1 H), 8.76 (d, J = 1.8 Hz, 1 H), 7.97 (d, J = 8.7 Hz, 1 H), 6.78 (d, J = 8.7 Hz, 1 H), 4.64-4.54 (m, 1 H), 4.31-4.21 (m, 1 H), 4.12-3.96 (m, 2 H), 3.76-3.62 (m, 5 H), 3.09-3.04 (m, 2 H), 2.71-2.59 (m, 1 H), 2.57-2.45 (m, 4 H), 1.12 (d, J = 6.8 Hz, 3 H).

Compound 8 (N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] -2- (1,4-dimethylpiperidine-4-yl) acetamide ): 8-[(3R, 4R) -3-amino-4-methylpyrrolidine-1-yl] quinoxalin-5-carbonitrile (43 mg, 0.17 mmol) and 2- (1,4-dimethylpiperidine-4-yl) Il) Purified from acetic acid by prep-HPLC under the following conditions: column, XBridge Prep C18 OBD column, 150 mm, 5 um, 13 nm; mobile phase, acetonitrile in water (containing 10 mM NH ₄ HCO ₃ ), 22% in 7 min. ~ 35% gradient; detector, UV 254 nm (12 mg, 17%, yellow solid). HPLC: 94.5% purity, RT = 4.31 min. MS: m / z = 407.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d _6, ppm) δ 8.91 (d, J = 1.8 Hz, 1 H), 8.80 (d, J = 1.8 Hz, 1 H), 8.01 (d, J = 8.7 Hz, 1 H), 7.89 (d, J = 8.3 Hz, 1 H), 6.71 (d, J = 8.8 Hz, 1 H), 4.52-4.39 (m, 1 H), 4.19-4.09 (m, 1 H), 3.97-3.90 (m, 1 H), 3.79-3.55 (m, 2 H), 2.47-1.93 (m, 10 H), 1.55-1.39 (m, 2 H), 1.31-1.25 (m, 2 H), 1.08-0.88 (m, 6 H).

Compound 15 ((2S) -N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] -2-hydroxy-3-methylbutaneamide): From 8-[(3R, 4R) -3-amino-4-methylpyrrolidine-1-yl] quinoxalin-5-carbonitrile and (2S) -2-hydroxy-3-methylbutanoic acid, prep-HPLC under the following conditions Purified by: column, XBridge Shield Prep C18 OBD column, 150 mm, 5 um, 13 nm; mobile phase, acetonitrile in water (containing 10 mmol / L NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), in 7 min. 30% -35% gradient; detector, UV 254 nm (29 mg, 27%, yellow solid). HPLC: 95.0% purity, RT = 3.35 min. MS: m / z = 354.3 [M + H] ⁺ . ^{1 1} H NMR (400 MHz, DMSO-d _6, ppm) δ 8.93 (d, J = 1.9 Hz, 1 H), 8.81 (d, J = 1.8 Hz, 1 H), 8.03 (d, J = 8.7 Hz, 1 H), 7.79 (d, J = 8.5 Hz, 1 H), 6.73 (d, J = 8.8 Hz, 1 H), 5.09 (d, J = 6.1 Hz, 1 H), 4.55-4.45 (m, 1) H), 4.21-4.12 (m, 1 H), 4.05-3.74 (m, 2 H), 3.71-3.58 (m, 2 H), 2.58-2.49 (m, 1 H), 1.98-1.85 (m, 1) H), 0.98 (d, J = 6.8 Hz, 3 H), 0.86 (d, J = 6.8 Hz, 3 H), 0.73 (d, J = 6.8 Hz, 3 H).

Compound 16 ((2R) -N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] -2-hydroxy-3-methylbutaneamide): From 8-[(3R, 4R) -3-amino-4-methylpyrrolidine-1-yl] quinoxalin-5-carbonitrile and (2R) -2-hydroxy-3-methylbutanoic acid, prep-HPLC under the following conditions Purified by: Column, XBride Shield Prep C18 OBD Column, 150 mm, 5 um, 13 nm; Mobile Phase, Acetonitrile in Water (containing 10 mmol / LNH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), in 7 min. 35% -39% gradient; detector, UV 254 nm (14 mg, 26%, yellow solid). HPLC: 96.1% purity, RT = 2.16 min. MS: m / z = 354.4 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 8.79 (d, J = 1.8 Hz, 1 H), 8.73 (d, J = 1.8 Hz, 1 H), 7.94 (d, J = 8.7 Hz, 1 H), 6.75 (d, J = 8.7 Hz, 1 H), 4.61-4.54 (m, 1 H), 4.30-4.18 (m, 1 H), 4.11-3.91 (m, 2 H), 3.86-3.78 (m, 1 H), 3.76-3.63 (m, 1 H), 2.66-2.57 (m, 1 H), 2.11-1.96 (m, 1 H), 1.10 (d, J = 6.8 Hz, 3 H), 0.96 (d, J = 6.9 Hz, 3 H), 0.86 (d, J = 6.8 Hz, 3 H).
Example 3: Compounds 3 and 4 (N-[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl) -4-methylpyrrolidine-3-yl] -2-[(3S) -1-methyl Piperidine-3-yl] acetamide and N-[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl) -4-methylpyrrolidine-3-yl] -2-[(3R) -1-methyl Synthesis of piperidine-3-yl] acetamide)

N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] -2-[(3S) -1-methylpiperidin-3-yl] acetamide and N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] -2-[(3R) -1-methylpiperidin-3-yl] acetamide: 2-((3R, 4R) -3-amino-4-methylpyrrolidine-1-yl] quinoxalin-5-carbonitrile (48 mg, 0.19 mmol) in N, N-dimethylformamide (4 mL) solution 1-Methylpyrrolidine-3-yl) acetic acid (59 mg, 0.38 mmol), HATU (144 mg, 0.38 mmol) and DIEA (147 mg, 1.14 mmol) were added at room temperature. The resulting solution was stirred at room temperature for 14 hours. When the reaction was completed, it was stopped by the addition of water (15 mL). The resulting mixture was extracted with DCM (30 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was first purified by prep-HPLC under the following conditions: column, XBride C18 OBD Prep column, 150 mm, 5 um; mobile phase, acetonitrile in water (containing 10 mM NH ₄ HCO ₃ ), 8 min. 25% -31% gradient in; detector, UV 254 nm. Two diastereomers were then obtained by separation on chiral prep-HPLC under the following conditions: column, CHIRALPAK IG, 2x15 cm, 3 um; mobile phase, 100% MeOH (containing 0.1% DEA) at 20 min; Vessel, UV 254 nm.

Isomer 1: (18 mg, 25%, yellow solid) HPLC: 90.3% purity, RT = 3.55 min. MS: m / z = 393.4 [M + H] ⁺ . ¹ H NMR (400 MHz, methanol-d _4, ppm) δ 8.82 (d, J = 1.7 Hz, 1 H), 8.76 (d, J = 1.8 Hz, 1 H), 7.96 (d, J = 8.7 Hz, 1 H), 6.77 (d, J = 8.7 Hz, 1 H), 4.62-4.57 (m, 1 H), 4.32-4.22 (m, 1 H), 4.09-3.94 (m, 2 H), 3.75-3.65 (m, 1 H), 2.92-2.78 (m, 2 H), 2.68-2.56 (m, 1 H), 2.27 (s, 3 H), 2.18-2.11 (m, 2 H), 2.04-1.99 (m) , 2 H), 1.84-1.64 (m, 3 H), 1.64-1.53 (m, 1 H), 1.11 (d, J = 6.8 Hz, 3 H), 1.03-0.90 (m, 1 H).

Isomer 2: (11 mg, 13%, yellow solid) HPLC: 95.3% purity, RT = 5.07 min. MS: m / z = 393.1 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 8.83-8.69 (m, 2 H), 7.94 (d, J = 8.7 Hz, 1 H), 6.74 (d, J = 8.8 Hz, 1 H) , 4.60-4.53 (m, 1 H), 4.30-4.18 (m, 1 H), 4.08-3.89 (m, 2 H), 3.74-3.60 (m, 1 H), 3.04-2.97 (m, 2 H) , 2.67-2.51 (m, 1 H), 2.40 (s, 3 H), 2.32-1.96 (m, 6 H), 1.82-1.72 (m, 2 H), 1.67-1.56 (m, 1 H), 1.30 -0.85 (m, 4 H).

The following compounds were synthesized in a similar manner:

Compounds 5 and 6 (N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] -2-[(3S) -1-methylpyrrolidine-3) -Il] Acetamide and N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] -2-[(3R) -1-methylpyrrolidine-3 -Il] acetamide): 8-[(3R, 4R) -3-amino-4-methylpyrrolidine-1-yl] from quinoxalin-5-carbonitrile and 2- (1-methylpyrrolidin-3-yl) acetic acid Purified by prep-HPLC under the following conditions: column, XBridge C18 OBD Prep column, 150 mm, 5 um; mobile phase, acetonitrile in water (containing 10 mM NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O),. 15% -45% gradient at 8 min; detector, UV 254 nm. Two diastereomers were obtained by separation on chiral prep-HPLC under the following conditions: column, CHIRALPAK IC-3, 0.46x10 cm, 3 um; mobile phase, MtBE (0) in methanol at 70% uniform concentration at 30 min. .Contains 1% DEA); Detector, UV 254 nm. Isomer 1: (13 mg, 15%, yellow solid) HPLC: 97.3% purity, RT = 3.00 min. MS: m / z = 379.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d _6, ppm) δ 8.91 (d, J = 1.8 Hz, 1 H), 8.80 (d, J = 1.8 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 2 H), 6.71 (d, J = 8.8 Hz, 1 H), 4.51-4.40 (m, 1 H), 4.15-4.08 (m, 1 H), 3.96-3.89 (m, 1 H), 3.80-3.73 (m, 1 H), 3.61-3.54 (m, 1 H), 2.37-2.26 (m, 5 H), 2.23-1.98 (m, 6 H), 1.91-1.75 (m, 1 H), 1.36-1.21 (m, 1 H), 0.94 (d, J = 6.8 Hz, 3 H). Isomer 2: (15 mg, 16%, yellow solid) HPLC: 94.1% purity, RT = 4.39 min. MS: m / z = 379.3 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 8.82-8.69 (m, 2 H), 7.93 (d, J = 8.7 Hz, 1 H), 6.73 (d, J = 8.7 Hz, 1 H) , 4.59-4.52 (m, 1 H), 4.29-4.17 (m, 1 H), 4.08-3.88 (m, 2 H), 3.73-3.60 (m, 1 H), 2.80-2.68 (m, 1 H) , 2.66-2.52 (m, 4 H), 2.33-2.17 (m, 6 H), 2.14-1.95 (m, 1 H), 1.57-1.39 (m, 1 H), 1.07 (d, J = 6.8 Hz, 3 H).

Compounds 13 and 14 ((2S) -N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidin-3-yl] -2-cyclopropyl-2-hydroxyacetoamide And (2R) -N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidin-3-yl] -2-cyclopropyl-2-hydroxyacetoamide): 8- [(3R, 4R) -3-amino-4-methylpyrrolidin-1-yl] prep from quinoxalin-5-carbonitrile (52 mg, 0.20 mmol) and 2-cyclopropyl-2-hydroxyacetic acid under the following conditions: -Purified by HPLC: column, XBridge Compound C18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water (containing 10 mmol / L NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 5 in 7 min. % -62% gradient; detector, UV 254 nm. Two diastereomers obtained by separation on chiral prep-HPLC under the following conditions: column, CHIRALPAK IA-3, 0.46x5 cm, 3 um; mobile phase, hexane in 50% uniform concentration EtOH at 15 min (0. Contains 1% DEA); detector, UV 254 nm. Isomer 1: (20 mg, 27%, yellow solid) HPLC: 96.1% purity, RT = 1.17 min. MS: m / z = 352.2 [M + H] ⁺ . ^{1 1} H NMR (400 MHz, DMSO-d _6, ppm) δ 8.93 (d, J = 1.8 Hz, 1 H), 8.82 (d, J = 1.8 Hz, 1 H), 8.04 (d, J = 8.7 Hz, 1 H), 7.78 (d, J = 8.5 Hz, 1 H), 6.74 (d, J = 8.8 Hz, 1 H), 5.09 (d, J = 6.1 Hz, 1 H), 4.52-4.47 (m, 1) H), 4.21-4.16 (m, 1 H), 4.00-3.95 (m, 1 H), 3.89-3.81 (m, 1 H), 3.62-3.57 (m, 1 H), 3.45 (t, J = 6.4 Hz, 1 H), 2.61-2.50 (m, 1 H), 1.08-0.95 (m, 4 H), 0.40-0.22 (m, 4 H). Isomer 2: (11 mg, 13%, yellow solid) HPLC: 97.4% purity, RT = 1.19 min. MS: m / z = 352.2 [M + H] ⁺ . ^{1 1} H NMR (400 MHz, DMSO-d _6, ppm) δ 8.94 (d, J = 1.7 Hz, 1 H), 8.83 (d, J = 1.7 Hz, 1 H), 8.05 (d, J = 8.6 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 1 H), 6.74 (d, J = 8.7 Hz, 1 H), 5.28 (d, J = 5.7 Hz, 1 H), 4.56-4.46 (m, 1) H), 4.25-4.15 (m, 1 H), 4.03-3.94 (m, 1 H), 3.91-3.83 (m, 1 H), 3.67-3.53 (m, 2 H), 2.61-2.52 (m, 1) H), 1.12-1.02 (m, 1 H), 1.00 (d, J = 6.8 Hz, 3 H), 0.41-0.25 (m, 4 H).
Example 4: Compound 9 (N-[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl) -4-methylpyrrolidine-3-yl] -2- (4-fluoropiperidine-4-yl) Synthesis of acetamide)

tert-Butyl 4-([[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] carbamoyl] methyl) -4-fluoropiperidine-1-carboxylate : 8-[(3R, 4R) -3-amino-4-methylpyrrolidine-1-yl] quinoxalin-5-carbonitrile (129 mg, 0.51 mmol) in a DCM (8 mL) solution of 2- [1-[( tert-Butoxy) carbonyl] -4-fluoropiperidin-4-yl] acetic acid (266 mg, 1.02 mmol), HATU (388 mg, 1.02 mmol) and DIEA (394 mg, 3.06 mmol) were added at room temperature. The resulting solution was stirred for 16 hours at room temperature. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBride Prep C18 OBD column, 150 mm, 5 um, 13 nm; mobile phase, acetonitrile in water (10 mM NH _4). Contains HCO ₃ and 0.1% NH ₃ .H ₂ O), 40% -53% gradient at 7 min; detector, UV 254 nm. 4-([[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl) -4-methylpyrrolidine-3-yl] carbamoyl] methyl) -4-fluoropiperidine-1-carboxylate as a yellow solid Obtained as (76 mg, 30%). MS: m / z = 497.3 [M + H] ⁺ .

N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] -2- (4-fluoropiperidin-4-yl) acetamide: tert-butyl 4 -([[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] carbamoyl] methyl) -4-fluoropiperidine-1-carboxylate (76 mg, 0) A hydrochloric acid solution (12N, 4 mL, 48 mmol) was added to a .15 mmol) MeOH (4 mL) solution at room temperature. The resulting solution was stirred at room temperature for 12 hours. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBride Prep C18 OBD column, 150 mm, 5 um, 13 nm; mobile phase, acetonitrile in water (10 mM NH). Contains ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 15% -42% gradient at 7 min; detector, UV 254 nm. N-[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl) -4-methylpyrrolidine-3-yl] -2- (4-fluoropiperidin-4-yl) acetamide as a yellow solid (13 mg) , 19%).

Compound 9: MS: m / z = 497.3 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d _6, ppm) δ 8.95 (d, J = 1.8 Hz, 1 H), 8.84 (d, J = 1.8 Hz, 1 H), 8.13-8.01 (m, 2 H) , 6.75 (d, J = 8.8 Hz, 1 H), 4.52-4.43 (m, 1 H), 4.26-3.86 (m, 2 H), 3.84-3.74 (m, 1 H), 3.62-3.52 (m, 1 H), 2.74-2.61 (m, 4 H), 2.50-2.36 (m, 3 H), 1.76-1.55 (m, 4 H), 1.00 (d, J = 6.8 Hz, 3 H).
Example 5: Compound 10 (N-[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl) -4-methylpyrrolidine-3-yl] -2- (4-fluoro-1-methylpiperidin-) 4-Il) Synthesis of acetamide)

N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] -2- (4-fluoro-1-methylpiperidine-4-yl) acetamide: N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] -2- (4-fluoropiperidin-4-yl) acetamide (32 mg, 0. To a solution of 08 mmol) in MeOH (3 mL) was added (HCHO) _n (44 mg, 0.49 mmol), NaOAC (135 mg, 1.64 mmol) and NaBH ₄ (15 mg, 0.41 mmol) at room temperature. The resulting solution was stirred at room temperature for 3 hours. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBride Shield RP18 OBD column, 150 mm, 5 um, 13 nm; mobile phase, acetonitrile in water (10 mM) Contains NH ₄ HCO ₃ ), 35% -65% gradient at 7 min; detector, UV 254 nm. N-[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl) -4-methylpyrrolidine-3-yl] -2- (4-fluoro-1-methylpiperidin-4-yl) acetamide yellow Obtained as a solid (7 mg, 21%).

Compound 10: HPLC: 90.3% purity, RT = 5.76 min. MS: m / z = 411.3 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 8.78 (d, J = 1.8 Hz, 1 H), 8.71 (d, J = 1.8 Hz, 1 H), 7.92 (d, J = 8.7 Hz, 1 H), 6.73 (d, J = 8.7 Hz, 1 H), 4.62-4.52 (m, 1 H), 4.31-4.16 (m, 1 H), 4.11-3.88 (m, 2 H), 3.73-3.59 (m, 1 H), 3.38-3.31 (m, 2 H), 3.22-3.06 (m, 2 H), 2.80 (s, 3 H), 2.73-2.52 (m, 3 H), 2.25-1.96 (m) , 4 H), 1.09 (d, J = 6.8 Hz, 3 H).
Example 6: Compounds 11 and 12 (N-[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl) -4-methylpyrrolidine-3-yl] -2-[(4S) -3,3 -Difluoro-1-methylpiperidine-4-yl] acetamide and N-[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl) -4-methylpyrrolidine-3-yl] -2-[( Synthesis of 4R) -3,3-difluoro-1-methylpiperidin-4-yl] acetamide)

tert-Butyl 4- (2-ethoxy-2-oxoethylidene) -3,3-dimethylpiperidine-1-carboxylate: 0 ^o C, ethyl (diethoxyphosphoryl) formalt (950 mg, 4.52 mmol) in THF ( Sodium hydride (102 mg, 4.25 mmol) was added to the 50 mL) solution at 0 ^o C. The resulting mixture was stirred for 15 minutes, and then tert-butyl 3,3-difluoro-4-oxopiperidin-1-carboxylate (798 mg, 3.39 mmol) was added at 0 ^o C. The reaction mixture was stirred at 0 ^o C for 0.5 h, warmed to room temperature and stirred at room temperature for 3 h. When the reaction was completed, it was stopped by the addition of water (20 mL). The resulting mixture was extracted with ethyl acetate (40 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent is removed under reduced pressure and the residue is purified by flash chromatography eluting with EtOAc (0% -50% gradient) in petroleum ether and tert-butyl 4- (2-ethoxy-2-oxoethylidene)-. 3,3-Dimethylpiperidine-1-carboxylate was produced as a colorless oil (560 mg, 35%). MS: m / z = 205.9 [M-100 + 1] ⁺ .

tert-Butyl 4- (2-ethoxy-2-oxoethyl) -3,3-difluoropiperidine-1-carboxylate: tert-butyl 4- (2-ethoxy-2-oxoethylidene) -3,3-difluoropiperidine- Palladium on carbon (138 mg, 0.13 mmol) was added to a solution of 1-carboxylate (1.11 g, 3.62 mmol) in EtOH (30 mL) under a nitrogen atmosphere. The reaction tank was evacuated and hydrogen was sprayed. The reaction mixture was then hydrogenated at room temperature using a balloon containing hydrogen for 3 hours in a hydrogen atmosphere. When the reaction is complete, the reaction mixture is filtered through a cellite pad, the filtrate is concentrated under reduced pressure and tert-butyl 4- (2-ethoxy-2-oxoethyl) -3,3-difluoropiperidine-1-carboxylate. Was produced as a colorless oil (1.01 g, 92%). MS: m / z = 207.9 [M-100 + 1] ⁺ .

2- [1-[(tert-butoxy) carbonyl] -3,3-difluoropiperidine-4-yl] acidic: tert-butyl 4- (2-ethoxy-2-oxoethyl) -3,3-difluoropiperidine-1 A potassium hydroxide solution (500 mg in 25 mL of water, 12.5 mmol) was added to a solution of −carboxylate (1.01 g, 3.29 mmol) in tetrahydrofuran (25 mL) at room temperature. The resulting mixture was stirred at 60 ^o C for 16 hours. When the reaction was complete, the reaction mixture was concentrated under vacuum. The pH value of the residue mixture was adjusted to 5 with hydrochloric acid solution (4N), and the resulting mixture was then extracted with ethyl acetate (50 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to produce 2- [1-[(tert-butoxy) carbonyl] -3,3-difluoropiperidine-4-yl] acetic acid as a colorless oil (504 mg, 42%). MS: m / z = 280.1 [M + H] ⁺ .

2-4-([[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] carbamoyl] methyl) -3,3-difluoropiperidine-1-carboxy Lat: 8-[(3R, 4R) -3-amino-4-methylpyrrolidine-1-yl] quinoxalin-5-carbonitrile (208 mg, 0.82 mmol) in a solution of 2- [1- [ (Tert-Butoxy) carbonyl] -3,3-difluoropiperidine-4-yl] acetic acid (581 mg, 2.08 mmol), HATU (620 mg, 1.63 mmol) and DIEA (633 mg, 4.90 mmol) added at room temperature. did. The resulting solution was stirred at room temperature for 1 h. When the reaction was completed, it was stopped by the addition of water (15 mL). The resulting mixture was extracted with ethyl acetate (50 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent is removed under reduced pressure and tert-butyl 4-([[(3R, 4R) -1- (8-cyanoquinoxaline-5-yl) -4-methylpyrrolidine-3-yl] carbamoyl] methyl) -3,3 -Difluoropiperidin-1-carboxylate was produced as a yellow solid (320 mg, crude product). MS: m / z = 515.3 [M + H] ⁺ .

N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] -2-[(4S) -3,3-difluoro-1-methylpiperidine- 4-yl] acetamide and N-[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] -2-[(4R) -3,3-difluoro -1-Methylpiperidin-4-yl] acetamide: tert-butyl 4-([[(3R, 4R) -1- (8-cyanoquinoxalin-5-yl) -4-methylpyrrolidine-3-yl] carbamoyl] Formalin (10%, 15 mL, 54 mmol) was added to a solution of methyl) -3,3-difluoropiperidine-1-carboxylate (320 mg, crude) HCOOH (26 mL) at room temperature. The resulting mixture was stirred at 140 ^o C for 1 h. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBride C18 OBD Prep column, 150 mm, 5 um; mobile phase, acetonitrile in water (10 mM NH _4). Contains HCO ₃ and 0.1% NH ₃ .H ₂ O), 30% -44% gradient at 8 min; detector, UV 254 nm. Two diastereomers were then obtained by separation on chiral prep-HPLC under the following conditions: column, CHIRALPAK IA-3, 0.46x5 cm, 3 um; mobile phase, hexane in ethanol at a uniform concentration of 50% at 15 min ( Contains 0.1% DEA), detector, UV 254 nm.

Isomer 1: (93 mg, 59%, yellow solid) HPLC: 93.2% purity, RT = 2.67 min. MS: m / z = 429.4 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 8.78 (d, J = 1.8 Hz, 1 H), 8.72 (d, J = 1.8 Hz, 1 H), 7.93 (d, J = 8.7 Hz, 1 H), 6.73 (d, J = 8.7 Hz, 1 H), 4.62-4.53 (m, 1 H), 4.30-4.17 (m, 1 H), 4.07-3.88 (m, 2 H), 3.73-3.60 (m, 1H), 3.03-2.97 (m, 1 H), 2.86-2.75 (m, 1 H), 2.69-2.50 (m, 2 H), 2.34-2.01 (m, 7 H), 1.85-1.72 ( m, 1 H), 1.60-1.42 (m, 1 H), 1.07 (d, J = 6.9 Hz, 3 H).

Isomer 2: (11 mg, 13%, yellow solid) HPLC: 93.1% purity, RT = 2.74 min. MS: m / z = 429.4 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 8.82-8.69 (m, 2 H), 7.93 (d, J = 8.7 Hz, 1 H), 6.73 (d, J = 8.7 Hz, 1 H) , 4.60-4.53 (m, 1 H), 4.31-4.18 (m, 1 H), 4.07-3.89 (m, 2 H), 3.73-3.60 (m, 1 H), 3.04-2.94 (m, 1 H) , 2.81-2.70 (m, 1 H), 2.69-2.50 (m, 2 H), 2.38-1.89 (m, 7 H), 1.79-1.68 (m, 1 H), 1.56-1.41 (m, 1 H) , 1.07 (d, J = 6.9 Hz, 3 H).
Example 7: Synthesis of compound 17 ((3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-amine)

tert-Butyl N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] carbamate: 5-bromo-8- (trifluoromethyl) ) Turt-butyl N-[(3R, 4R) -4-methylpyrrolidin-3-yl] carbamate (241 mg, 1.20 mmol) in a solution of quinoline (245 mg, 0.89 mmol) in N, N-dimethylformamide (5 mL). , Pd ₂ (dba) ₃ . CHCl ₃ (124 mg, 0.12 mmol), K ₃ PO ₄ (768 mg, 3.62 mmol) and Dave Phos (93 mg, 0.23 mmol) were added at room temperature. The resulting mixture was stirred at 130 ^o C for 3 h. When the reaction was complete, the solids in the reaction mixture were filtered off and the filtrate was diluted with water (20 mL). The resulting mixture was extracted with DCM (50 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solution is removed under reduced pressure and the residue is purified by flash chromatography eluting with EtOAc (0% -20% gradient) in hexanes with tert-butyl N-[(3R, 4R) -4-methyl-1- [8]. -(Trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] carbamate was produced as a brown solid (298 mg, 85%). MS: m / z = 396.2 [M + H] ⁺ .

(3R, 4R) -4-Methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-amine: tert-butyl N-[(3R, 4R) -4-methyl-1- [8- (Trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] Carbamate (50 mg, 0.13 mmol) in methanol (3 mL) and hydrochloric acid solution (6 M in dioxane, 2 mL, 12 mmol) at room temperature Added. The resulting solution was stirred for 2 hours at room temperature. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBridge Sheld Prep C18 OBD column, 150 mm, 5 um, 13 nm; mobile phase, acetonitrile in water ( Contains 10 mmol / L NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), gradient 30% to 51% at 7 min; detector, UV 254 nm. (3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-amine was obtained as a yellow solid (25 mg, 64%).

Compound 17: HPLC: 93.4% purity, RT = 2.08 min. MS: m / z = 296.0 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d _6, ppm) δ 8.89 (d, J = 3.9 Hz, 1 H), 8.70 (d, J = 8.8 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 1 H), 7.51-7.40 (m, 1 H), 6.67 (d, J = 8.5 Hz, 1 H), 3.92-3.80 (m, 1 H), 3.58-3.43 (m, 3H), 3.38-3.27 ( m, 1 H), 2.37-2.22 (m, 1 H), 1.03 (d, J = 6.8 Hz, 3 H).
Example 8: Compound 18 (N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] -2- (1-methylpiperidin-) 4-Il) Synthesis of acetamide)

N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] -2- (1-methylpiperidin-4-yl) acetamide: In a solution of (3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-amine (38 mg, 0.13 mmol) in N, N-dimethylformamide (3 mL). Add 2- (1-methylpiperidin-4-yl) acetic acid (63 mg, 0.40 mmol), DIEA (31 mg, 0.24 mmol) and HATU (307 mg, 0.81 mmol, 6.36 equivalents, 95%) at room temperature. did. The resulting solution was stirred for 3 hours at room temperature. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBride Shield Prep C18 OBD column, 150 mm, 5 um, 13 nm; mobile phase, acetonitrile in water ( Contains 10 mmol / L NH ₄ HCO ₃ and 0.1% NH _3. H ₂ O), 35% -42% gradient at 7 min; detector, UV 254 nm. N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] -2- (1-methylpiperidin-4-yl) acetamide Obtained as a yellow solid (25 mg, 44%).

Compound 18: HPLC: 98.4% purity, RT = 0.90 min. MS: m / z = 435.2 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d _6, ppm) δ 8.95-8.86 (m, 1 H), 8.69 (d, J = 8.8, 1.7 Hz, 1 H), 7.98-7.84 (m, 2 H), 7.54-7.43 (m, 1 H), 6.72 (d, J = 8.5 Hz, 1 H), 4.54-4.40 (m, 1 H), 4.04-3.92 (m, 1 H), 3.68-3.56 (m, 1) H), 3.58-3.45 (m, 1 H), 3.37-3.25 (m, 2 H), 2.74-2.60 (m, 2 H), 2.14-1.99 (m, 5 H), 1.78 (d, J = 9.4) Hz, 2 H), 1.61-1.44 (m, 3 H), 1.19-1.02 (m, 2 H), 0.97 (d, J = 6.8 Hz, 3 H).

The following compounds were synthesized in a similar manner:

Compound 23 (N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] -2- (morpholine-4-yl) acetate) : (3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-amine and 2- (morpholine-4-yl) acetic acid under the following conditions prep purified by the upper -HPLC: column, XBridge Shield Prep C18 OBD column, 150 mm, 5um, 13 nm; (containing _NH 3 .H ₂ O 0.05%) mobile phase, acetonitrile in water, 39% in 8min through 59% Gradient; detector, UV 254 nm (35 mg, 39%, yellow solid). HPLC: 96.3% purity, RT = 2.80 min. MS: m / z = 423.1 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d _6, ppm) δ 8.96-8.87 (m, 1 H), 8.70 (d, J = 8.8, 1.7 Hz, 1 H), 7.95-7.80 (m, 2 H), 7.55-7.44 (m, 1 H), 6.76 (d, J = 8.5 Hz, 1 H), 4.52-4.43 (m, 1 H), 4.01-3.89 (m, 1 H), 3.72-3.37 (m, 7) H), 3.06-2.88 (m, 2 H), 2.59-2.51 (m, 1 H), 2.47-2.37 (m, 4 H), 0.98 (d, J = 6.8 Hz, 3 H).

Compound 24 (2- (1,4-dimethylpiperidine-4-yl) -N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3 -Il] acetamide): (3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-amine (60 mg, 0.20 mmol) and 2- (1, Purified from 4-dimethylpiperidine-4-yl) acetic acid by prep-HPLC under the following conditions: column, XBridge Shield Prep C18 OBD column, 150 mm, 5 um, 13 nm; mobile phase, acetonitrile in water (10 mmol / L NH). Contains ₄ HCO ₃ and 0.1% NH _3. H ₂ O), gradient 40% to 52% at 10 min; detector, UV 254 nm (45 mg, 49%, yellow solid). HPLC: 98.4% purity, RT = 4.24 min. MS: m / z = 449.4 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d _6, ppm) δ 8.95-8.87 (m, 1 H), 8.70 (d, J = 8.8, 1.7 Hz, 1 H), 7.94-7.84 (m, 2 H), 7.55-7.44 (m, 1 H), 6.72 (d, J = 8.5 Hz, 1 H), 4.50-4.41 (m, 1 H), 4.04-3.92 (m, 1 H), 3.66-3.46 (m, 2) H), 3.40-3.30 (m, 1 H), 2.36-2.30 (m, 2 H), 2.22-1.99 (m, 8 H), 1.58-1.44 (m, 2 H), 1.34-1.27 (m, 2) H), 1.03-0.91 (m, 6 H).

Compound 31 ((2S) -2-hydroxy-3-methyl-N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] Butaneamide): From (3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-amine and (2S) -2-hydroxy-3-methylbutanoic acid, Purified by prep-HPLC under the conditions of: column, XBridge Shield Prep C18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water (10 mmol / L NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O). Included), 40% -56% gradient at 7 min; detector, UV 254 nm (42 mg, 53%, yellow solid). HPLC: 98.2% purity, RT = 4.89 min. MS: m / z = 396.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d _6, ppm) δ 8.94-8.86 (m, 1 H), 8.72 (d, J = 8.8, 1.7 Hz, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 8.5 Hz, 1 H), 7.53-7.42 (m, 1 H), 6.74 (d, J = 8.5 Hz, 1 H), 4.58-4.36 (m, 1 H), 3.96 -3.84 (m, 1 H), 3.72-3.60 (m, 2 H), 3.59-3.42 (m, 2 H), 2.60-2.49 (m, 1 H), 2.06-1.91 (m, 1 H), 0.97 ( d, J = 6.8 Hz, 3 H), 0.88 (d, J = 6.9 Hz, 3 H), 0.79 (d, J = 6.7 Hz, 3 H).

Compound 32 ((2R) -2-hydroxy-3-methyl-N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] Butanamide): (3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-amine (60 mg, 0.20 mmol) and (2S) -2-hydroxy- Purified from 3-methylbutanoic acid by prep-HPLC under the following conditions: column, XBridge Shield Prep C18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water (10 mmol / L NH ₄ HCO ₃ and 0.1%). NH _3. Contains H ₂ O), 40% -56% gradient at 7 min; detector, UV 254 nm (42 mg, 52%, yellow solid). HPLC: 97.6% purity, RT = 1.68 min. MS: m / z = 396.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, methanol-d _4, ppm) δ 8.89-8.80 (m, 1 H), 8.73 (d, J = 8.8, 1.7 Hz, 1 H), 7.91 (d, J = 8.5 Hz, 1 H), 7.53-7.42 (m, 1 H), 6.87 (d, J = 8.5 Hz, 1 H), 4.64-4.55 (m, 1 H), 4.03-3.86 (m, 2 H), 3.77-3.64 ( m, 1 H), 3.61-3.43 (m, 2 H), 2.75-2.59 (m, 1 H), 2.14-1.97 (m, 1 H), 1.11 (d, J = 6.9 Hz, 3 H), 0.98 (d, J = 6.9 Hz, 3 H), 0.80 (d, J = 6.8 Hz, 3 H).
Examples 9: Compounds 19 and 20 (N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] -2-[(3S)) -1-Methylpiperidin-3-yl] acetamide and N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] -2- Synthesis of [(3R) -1-methylpiperidin-3-yl] acetamide)

N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] -2-[(3S) -1-methylpiperidin-3-3 Il] acetamide and N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] -2-[(3R) -1-methyl Piperidine-3-yl] acetamide: N, N of (3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-amine (119 mg, 0.40 mmol) -Dimethylformamide (5 mL) solution with 2- (1-methylpyrrolidine-3-yl) acetic acid (152 mg, 0.97 mmol), DIEA (76 mg, 0.59 mmol) and HATU (735 mg, 1.93 mmol) at room temperature. Was added. The resulting mixture was stirred for 3 hours at room temperature. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was first purified by prep-HPLC under the following conditions: column, XBride Prep C18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water (10 mmol / L). Contains NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 40% -70% gradient at 7 min; detector, UV 254 nm. Two diastereomers were then obtained by separation on chiral prep-HPLC under the following conditions: column, CHIRALPAK IG, 0.46x15 cm, 3 um; mobile phase, hexane in EtOH at a uniform concentration of 88% at 30 min (0. Contains 1% DEA); detector, UV 254 nm.

Isomer 1: (20 mg, 11%, yellow solid) HPLC: 97.8% purity, RT = 2.39 min. MS: m / z = 435.3 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d _6, ppm) δ 8.95 --8.87 (m, 1 H), 8.70 (d, J = 8.8, 1.7 Hz, 1 H), 8.00-7.85 (m, 2 H), 7.55-7.44 (m, 1 H), 6.73 (d, J = 8.5 Hz, 1 H), 4.58-4.37 (m, 1 H), 4.04-3.92 (m, 1 H), 3.69-3.57 (m, 1) H), 3.59-3.46 (m, 1 H), 3.38-3.27 (m, 1 H), 2.62-2.51 (m, 3 H), 2.14-1.94 (m, 5 H), 1.88-1.73 (m, 2) H), 1.65-1.48 (m, 3 H), 1.44-1.33 (m, 1 H), 0.97 (d, J = 6.7 Hz, 3 H), 0.91-0.74 (m, 1 H).

Isomer 2: (25 mg, 14%, yellow solid) HPLC: 99.5% purity, RT = 1.25 min. MS: m / z = 435.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d _6, ppm) δ 8.94-8.86 (m, 1 H), 8.69 (d, 1 H), 7.99-7.83 (m, 2 H), 7.54-7.43 (m, 1) H), 6.72 (d, J = 8.6 Hz, 1 H), 4.50-4.41 (m, 1 H), 4.04-3.92 (m, 1 H), 3.67-3.55 (m, 1 H), 3.58-3.45 ( m, 1 H), 3.37-3.25 (m, 2 H), 2.62-2.52 (m, 2 H), 2.12-1.97 (m, 5 H), 1.921.73 (m, 2 H), 1.60-1.49 ( m, 3 H), 1.45-1.34 (m, 1 H), 0.96 (d, J = 6.8 Hz, 3 H), 0.88-0.78 (m, 1 H).

The following compounds were synthesized in a similar manner:

Compounds 21 and 22 (N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] -2-[(3S) -1- Methylpyrrolidine-3-yl] acetamide and N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] -2-[(3R) ) -1-Methylpyrrolidine-3-yl] acetamide): (3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-amine (109 mg, 0. Purified from 37 mmol) and 2- (1-methylpyrrolidine-3-yl) acetic acid by prep-HPLC under the following conditions: column, XBride Prep C18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water (0). .05% NH ₃ .H ₂ O contained), 39% -54% gradient at 8 min; detector, UV 254 nm. Two diastereomers were obtained by separation on chiral prep-HPLC under the following conditions: column, CHIRALPAK IC-3, 0.46x15 cm, 3 um; mobile phase, hexane in IPA at 50% uniform concentration at 30 min (0). .Contains 1% DEA); Detector, UV 254 nm. Isomer 1: (20 mg, 11%, yellow solid) HPLC: 99.5% purity, RT = 2.87 min. MS: m / z = 421.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d _6, ppm) δ 8.95-8.86 (m, 1 H), 8.69 (d, J = 8.7, 1.7 Hz, 1 H), 7.98 (d, J = 8.3 Hz, 1 H), 7.88 (d, J = 8.5 Hz, 1 H), 7.54-7.43 (m, 1 H), 6.72 (d, J = 8.5 Hz, 1 H), 4.50-4.41 (m, 1 H), 4.03 -3.91 (m, 1 H), 3.67-3.45 (m, 2 H), 3.37-3.27 (m, 1 H), 2.58-2.30 (m, 5 H), 2.26-2.01 (m, 6 H), 1.91 -1.73 (m, 1 H), 1.39-1.21 (m, 1 H), 0.96 (d, J = 6.7 Hz, 3 H). Isomer 2: (20 mg, 11%, yellow solid) HPLC: 98.8% purity, RT = 2.88 min. MS: m / z = 421.1 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d _6, ppm) δ 8.94-8.86 (m, 1 H), 8.74-8.64 (m, 1 H), 7.99 (d, J = 8.3 Hz, 1 H), 7.88 ( d, J = 8.5 Hz, 1 H), 7.54-7.43 (m, 1 H), 6.72 (d, J = 8.5 Hz, 1 H), 4.49-4.42 (m, 1 H), 4.04-3.92 (m, 1 H), 3.67-3.45 (m, 2 H), 3.36-3.29 (m, 1 H), 2.59-2.33 (m, 5 H), 2.28-2.05 (m, 6 H), 1.97-1.79 (m, 1 H), 1.44-1.26 (m, 1 H), 0.96 (d, J = 6.8 Hz, 3 H).

Compounds 29 and 30 ((2S) -2-cyclopropyl-2-hydroxy-N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3) -Il] acetamide and (2R) -2-cyclopropyl-2-hydroxy-N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3 -Il] acetamide): (3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-amine and 2-cyclopropyl-2-hydroxyacetic acid, Purified by prep-HPLC under the conditions of: column, XBridge Prep C18 OBD column, 150 mm, 5 um; mobile phase, containing acetonitrile in water (10 mmol / L NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O). ), Gradient at 7 min 35% to 52%; detector, UV 254 nm. Two diastereomers were obtained by separation on chiral prep-HPLC under the following conditions: column, CHIRALPAK IA-3, 0.46x15 cm, 3 um; mobile phase, hexane in 90% uniform concentration EtOH at 30 min (0). .1% DEA content) ,; Detector, UV 254 nm. Isomer 1: (25 mg, 19%, yellow solid) HPLC: 99.8% purity, RT = 1.59 min. MS: m / z = 394.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, DMSO-d _6, ppm) δ 8.94-8.86 (m, 1 H), 8.71 (d, J = 8.7, 1.7 Hz, 1 H), 7.89 (d, J = 8.5 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 7.54-7.43 (m, 1 H), 6.73 (d, J = 8.5 Hz, 1 H), 4.53-4.46 (m, 1 H), 4.02 -3.89 (m, 1 H), 3.72-3.60 (m, 1 H), 3.55-3.40 (m, 3 H), 2.60-2.51 (m, 1 H), 1.09-0.93 (m, 4 H), 0.43 -0.21 (m, 4 H). Isomer 2: (18 mg, 10%, yellow solid) HPLC: 99.7% purity, RT = 2.30 min. MS: m / z = 394.1 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, methanol-d _4, ppm) δ 8.89-8.80 (m, 1 H), 8.75 (d, J = 8.8, 1.7 Hz, 1 H), 7.91 (d, J = 8.4 Hz, 1 H), 7.53-7.42 (m, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 4.66-4.59 (m, 1 H), 4.03-3.91 (m, 1 H), 3.76-3.63 ( m, 2 H), 3.60-3.43 (m, 2 H), 2.75-2.59 (m, 1 H), 1.24-1.07 (m, 4 H), 0.57-0.37 (m, 4 H).
Example 10: Compound 25 (2- (4-fluoropiperidin-4-yl) -N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine- 3-Il] acetamide) synthesis

tert-Butyl 4-fluoro-4-([[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] carbamoyl] methyl) piperidine- 1-carboxylate: N, N-dimethylformamide of (3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-amine (48 mg, 0.16 mmol) 2- [1-[(tert-butoxy) carbonyl] -4-fluoropiperidin-4-yl] acetic acid (82 mg, 0.31 mmol), DIEA (31 mg, 0.24 mmol) and HATU (307 mg,) in solution (1 mL). 0.81 mmol) was added at room temperature. The resulting solution was stirred at room temperature for 3 hours. When the reaction was complete, the reaction mixture was diluted with water (10 mL) and the resulting mixture was extracted with ethyl acetate (30 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent is removed under reduced pressure and tert-butyl 4-fluoro-4- ([[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl]]. Carbamoyl] methyl) piperidine-1-carboxylate was produced as a yellow solid (80 mg, crude product).

2- (4-Fluoropiperidin-4-yl) -N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] acetamide: tert-Butyl 4-fluoro-4-([[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] carbamoyl] methyl) piperidine- A hydrochloric acid solution (6N in dioxane, 2 mL, 12 mmol) was added to a solution of 1-carboxylate (80 mg, crude product) in methanol (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBride Sheld Prep C18 OBD column, 150 mm, 5 um, 13 nm; mobile phase, in water. Acetonitrile (containing 10 mmol / L NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), gradient 32% -38% at 7 min; detector, UV 254 nm. 2- (4-Fluoropiperidin-4-yl) -N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] acetamide yellow Obtained as a solid (12 mg, 1.3% in steps).

Compound 25: HPLC: 95.2% purity, RT = 2.93 min. MS: m / z = 439.4 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d _6, ppm) δ 8.86-8.78 (m, 1 H), 8.61 (d, J = 8.8 Hz, 1 H), 7.80 (d, J = 8.5 Hz, 1 H) , 7.67 (d, J = 7.5 Hz, 1 H), 7.45-7.34 (m, 1 H), 6.70 (d, J = 8.4 Hz, 1 H), 4.52-4.43 (m, 1 H), 4.10-3.90 (m, 1 H), 3.63-3.45 (m, 3 H), 2.81-2.60 (m, 4 H), 2.40-2.20 (m, 4 H), 1.85-1.55 (m, 4 H), 1.05-0.85 (m, 3 H).
Example 11: Compound 26 (2- (4-fluoro-1-methylpiperidine-4-yl) -N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-) Synthesis of yl] pyrrolidine-3-yl] acetamide)

2- (4-Fluoro-1-methylpiperidin-4-yl) -N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl Il] Acetamide: 2- (4-fluoropiperidin-4-yl) -N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] Il] Acetamide (48 mg, 0.11 mmol) in methanol (3 mL) with (CH ₂ O) _n (95 mg, 1.05 mmol), NaOAC (190 mg, 2.32 mmol) and NaBH ₄ (66 mg, 1.76 mmol). Added at room temperature. The resulting mixture was stirred at room temperature for 12 hours. When the reaction was completed, it was stopped by the addition of water (5 mL). The resulting mixture was extracted with ethyl acetate (30 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBridge Shield Prep C18 OBD column, 150 mm, 5 um, 13 nm; mobile phase, acetonitrile in water (10 mmol / L NH ₄ HCO _3). and containing _{0.1% NH 3 .H 2 O)} , 30% ~55% gradient in 7min; detector, UV 254 nm. 2- (4-Fluoro-1-methylpiperidin-4-yl) -N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl Il] Acetamide was obtained as a yellow solid (20 mg, 40%).

Compound 26: HPLC: 98.3% purity, RT = 3.39 min. MS: m / z = 453.5 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, methanol-d _4, ppm) δ 8.88-8.79 (m, 1 H), 8.74 (d, J = 8.8, 1.7 Hz, 1 H), 7.90 (d, J = 8.5 Hz, 1 H), 7.51-7.40 (m, 1 H), 6.83 (d, J = 8.5 Hz, 1 H), 4.65-4.54 (m, 1 H), 4.05-3.93 (m, 1 H), 3.72-3.60 ( m, 1H), 3.62-3.49 (m, 1 H), 3.47-3.36 (m, 1 H), 2.74-2.45 (m, 5 H), 2.40-2.26 (m, 5 H), 1.95-1.89 (m) , 3 H), 1.98-1.75 (m, 1 H), 1.09 (d, J = 6.8 Hz, 3 H).
Examples 12: Compounds 27 and 28 (2-[(4S) -3,3-difluoro-1-methylpyrrolidine-4-yl] -N-[(3R, 4R) -4-methyl-1- [8-( Trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] acetamide and 2-[(4R) -3,3-difluoro-1-methylpiperidin-4-yl] -N-[(3R, 4R)- Synthesis of 4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] acetamide)

tert-butyl 3,3-difluoro-4- ([[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] carbamoyl] methyl) Piperidine-1-carboxylate: (3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-amine (50 mg, 0.17 mmol) in dichloromethane (3 mL) 2- [1-[(tert-butoxy) carbonyl] -3,3-difluoropiperidin-4-yl] acetic acid (62 mg, 0.22 mmol), DIEA (32 mg, 0.24 mmol) and HATU (307 mg, 0) in solution. .81 mmol) was added at room temperature. The resulting solution was stirred at room temperature for 3 hours. When the reaction was completed, it was stopped by the addition of water (10 mL). The resulting mixture was extracted with ethyl acetate (50 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was concentrated under reduced pressure and 3,3-difluoro-4- ([[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] ] Carbamoyl] methyl) piperidine-1-carboxylate was produced as a yellow solid (80 mg, crude product). MS: m / z = 557.5 [M + H] ⁺ .

tert-butyl 3,3-difluoro-4- ([[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] carbamoyl] methyl) Piperidine-1-carboxylate: tert-butyl 3,3-difluoro-4-([[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl] pyrrolidine-3] A solution of hydrochloric acid (6N in dioxane, 2 mL, 12 mmol) was added to a solution of −yl] carbamoyl] methyl) piperidine-1-carboxylate (80 mg, crude product) in methanol (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. When the reaction was completed, it was stopped by the addition of water (10 mL). The pH value of the resulting mixture was adjusted to 8 with a saturated NaHCO ₃ solution. The resulting mixture was extracted with ethyl acetate (50 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and 2- (3,3-difluoropiperidin-4-yl) -N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-yl) ] Pyrrolidine-3-yl] Acetamide was produced as a yellow solid (60 mg, crude product). MS: m / z = 557.5 [M + H] ⁺ .

2-[(4S) -3,3-difluoro-1-methylpiperidin-4-yl] -N-[(3R, 4R) -4-methyl-1- [8- (trifluoromethyl) quinoline-5-] Il] pyrrolidine-3-yl] acetamide and 2-[(4R) -3,3-difluoro-1-methylpiperidine-4-yl] -N-[(3R, 4R) -4-methyl-1- [8] -(Trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] acetamide: 2- (3,3-difluoropiperidine-4-yl) -N-[(3R, 4R) -4-methyl-1- [8- (Trifluoromethyl) quinoline-5-yl] pyrrolidine-3-yl] acetamide (60 mg, crude) in a solution of (CH ₂ O) _n (110 mg, 2.45 mmol) in methanol (4 mL), NaOAc ( 200 mg (4.86 mmol) and NaBH ₄ (72 mg, 3.79 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 16 hours. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was first purified by prep-HPLC under the following conditions: column, XBride Prep C18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water (10 mmol /). Contains L NH ₄ HCO ₃ and 0.1% NH _3. H ₂ O), 35% -50% gradient at 8 min; detector, UV 254 nm. Two diastereomers were then obtained by separation on chiral prep-HPLC under the following conditions: column, CHIRALPAK IC-3, 0.46x15 cm, 3 um; mobile phase, hexane in IPA at a uniform concentration of 50% at 20 min ( Contains 0.1% DEA); detector, UV 254 nm.

Isomer 1: (12 mg, 15% in 3 steps, grayish white solid) HPLC: 99.0% purity, RT = 3.06 min. MS: m / z = 471.5 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d _6, ppm) δ 8.96-8.87 (m, 1 H), 8.75-8.65 (m, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 7.90 ( d, J = 8.4 Hz, 1 H), 7.55-7.44 (m, 1 H), 6.73 (d, J = 8.5 Hz, 1 H), 4.51-4.42 (m, 1 H), 4.06-3.94 (m, 1 H), 3.68-3.46 (m, 2 H), 2.98-2.86 (m, 1 H), 2.67-2.56 (m, 1 H), 2.50-2.44 (m, 2 H), 2.29-2.02 (m, 7 H), 1.98-1.84 (m, 1 H), 1.64-1.52 (m, 1 H), 1.38-1.20 (m, 1 H), 0.98 (d, J = 6.7 Hz, 3 H).

Isomer 2: (12 mg, 15% in 3 steps, yellow solid) HPLC: 99.5% purity, RT = 3.01 min. MS: m / z = 471.5 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d _6, ppm) δ 9.01-8.93 (m, 1 H), 8.83-8.71 (m, 1 H), 8.20 (d, J = 8.4 Hz, 1 H), 7.95 ( d, J = 8.5 Hz, 1 H), 7.61-7.50 (m, 1 H), 6.79 (d, J = 8.6 Hz, 1 H), 4.64-4.40 (m, 1 H), 4.10 --3.98 (m, 1 H), 3.74-3.62 (m, 1 H), 3.65-3.52 (m, 1 H), 3.14-2.83 (m, 2 H), 2.82-2.71 (m, 1 H), 2.53-2.47 (m, 1 H), 2.38-1.88 (m, 8 H), 1.81-1.70 (m, 1 H), 1.52-1.34 (m, 1 H), 1.02 (d, J = 6.7 Hz, 3 H).
Example 13: Synthesis of compound 33 ((3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-amine)

5-Bromo-8-methylquinoline: 3,3-diethoxyprop-1-ene (1.) in a mixture of 5-bromo-2-methylaniline (980 mg, 5.27 mmol) in HCl solution (2M, 30 mL). 67 g, 12.80 mmol) was added at room temperature. The resulting mixture was stirred at 110 ^o C for 16 h. When the reaction was complete, the pH value of the reaction mixture was adjusted to 7-8 with sodium bicarbonate solution (4M). The resulting mixture was extracted with DCM (100 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent is removed under reduced pressure and the residue is purified by flash chromatography eluting with EtOAc (0% -70% gradient) in hexanes to produce 5-bromo-8-methylquinoline as a yellow solid (360 mg, 30%). did. MS: m / z = 223.9 [M + H] ⁺ .

tert-Butyl N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] Carbamate: 5-bromo-8-methylquinolin (360 mg, 1.62 mmol) ) In a solution of N, N-dimethylformamide (10 mL), tert-butyl N-[(3R, 4R) -4-methylpyrrolidine-3-yl] carbamate (342 mg, 1.71 mmol), Pd ₂ (dba) ₃ CHCl. ₃ (177mg, _0.17mmol), was _{K 3 PO 4 (1088mg, 5.12mmol} ) and Davephos (135mg, 0.34mmol) was added at room temperature. The resulting mixture was stirred at 130 ^o C for 3 h. When the reaction was completed, it was stopped by the addition of water (20 mL). The resulting mixture was extracted with DCM (100 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent is removed under reduced pressure and the residue is purified by flash chromatography eluting with EtOAc (0% -25% gradient) in hexanes and tert-butyl N-[(3R, 4R) -4-methyl-1-( 8-Methylquinoline-5-yl) pyrrolidine-3-yl] carbamate was produced as yellow oil (400 mg, 72%). MS: m / z = 342.2 [M + H] ⁺ .

(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-amine: tert-butyl N-[(3R, 4R) -4-methyl-1- (8-methyl) Kinolin-5-yl) pyrrolidine-3-yl] carbamate (200 mg, 0.59 mmol) was added to a solution of methanol (5 mL) in hydrochloric acid (4 M in dioxane, 3 mL, 12 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified on prep-HPLC under the following conditions: column, XBride Sheld Prep C18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water ( Contains 10 mmol / L NH ₄ HCO ₃ and 0.1% NH _3. H ₂ O), 5% -60% gradient at 7 min; detector, UV 254 nm. (3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-amine was obtained as a yellow solid (60 mg, 42%).

Compound 33: HPLC: 99.5% purity, RT = 1.07 min. MS: m / z = 242.3 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, methanol-d _4, ppm) δ 8.82-8.74 (m, 1 H), 8.71-8.61 (m, 1 H), 7.48-7.37 (m, 2 H), 6.92 (d, J) = 7.9 Hz, 1 H), 3.77-3.65 (m, 1 H), 3.62-3.51 (m, 1 H), 3.50-3.38 (m, 1 H), 3.37-3.25 (m, 1 H), 3.23- 3.12 (m, 1 H), 2.63 (s, 3 H), 2.56-2.40 (m, 1 H), 1.14 (d, J = 7.0 Hz, 3 H).
Example 14: Compound 34 (N-[(3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-yl] -2- (1-methylpiperidin-4-yl) Acetamide) synthesis

N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] -2- (1-methylpiperidin-4-yl) acetamide: (3R, 4R) ) -4-Methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-amine (40 mg, 0.16 mmol) in 2- (1-methylpiperidin-4-) solution of N-dimethylformamide (2 mL). Il) Acetamide (38 mg, 0.24 mmol), HATU (91 mg, 0.24 mmol) and DIEA (101 mg, 0.78 mmol) were added at room temperature. The resulting solution was stirred for 14 hours. When the reaction was complete, the reaction mixture was depressurized or concentrated, concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBride Sheld Prep C18 OBD column, 150 mm, 5 um; mobile phase, in water. Acetonitrile (containing 10 mmol / L NH ₄ HCO ₃ and 0.1% NH _3. H ₂ O), 5% to 61% gradient at 7 min; detector, UV 254 nm. N-[(3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-yl] -2- (1-methylpiperidin-4-yl) acetamide as a yellow solid (20 mg) , 31%).

Compound 34: HPLC: 97.4% purity, RT = 2.79 min. MS: m / z = 381.4 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 8.84-8.75 (m, 1 H), 8.73-8.59 (m, 1 H), 7.50-7.39 (m, 2 H), 6.96 (d, J) = 7.8 Hz, 1 H), 4.68-4.56 (m, 1 H), 3.80-3.68 (m, 1 H), 3.51-3.39 (m, 1 H), 3.32-3.19 (m, 1 H), 3.21- 3.10 (m, 1 H), 2.90-2.78 (m, 2 H), 2.71-2.52 (m, 4 H), 2.30-2.12 (m, 5 H), 2.09-1.93 (m, 2 H), 1.88- 1.62 (m, 3 H), 1.42-1.17 (m, 2 H), 1.06 (d, J = 7.0 Hz, 3 H).

The following compounds were synthesized in a similar manner:

Compound 39 (N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] -2- (morpholine-4-yl) acetate): (3R, Purified from 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-amine and 2- (morpholine-4-yl) acetic acid by prep-HPLC under the following conditions: Column, XBridge Shield Prep C18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water (containing 10 mmol / L NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 20% -50% gradient at 8 min; Detector, UV 254 nm (20 mg, 24%, yellow solid). HPLC: 99.1% purity, RT = 1.29 min. MS: m / z = 369.4 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 8.85-8.76 (m, 1 H), 8.69-8.59 (m, 1 H), 7.52-7.41 (m, 2 H), 7.00 (d, J) = 7.8 Hz, 1 H), 4.66-4.54 (m, 1 H), 3.81-3.64 (m, 5 H), 3.50-3.37 (m, 1 H), 3.31-3.11 (m, 3 H), 3.12- 2.99 (m, 2 H), 2.78-2.57 (m, 4 H), 2.62-2.45 (m, 4 H), 1.08 (d, J = 7.0 Hz, 3 H).

Compound 40 (2- (1,4-dimethylpiperidine-4-yl) -N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] acetamide ): From (3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-amine and 2- (1,4-dimethylpiperidine-4-yl) acetic acid, the following conditions Purified by lower prep-HPLC: column, XBridge Shield Prep C18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water (containing 10 mmol / L NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O). , 30% -60% gradient at 8 min; detector, UV 254 nm (10 mg, 15%, pale yellow solid). HPLC: 97.3% purity, RT = 2.30 min. MS: m / z = 395.4 [M + H] ⁺ . ¹ H NMR (300 MHz, DMSO-d _6, ppm) δ 8.83-8.74 (m, 1 H), 8.54-8.44 (m, 1 H), 7.83 (d, J = 8.3 Hz, 1 H), 7.42- 7.31 (m, 2 H), 6.77 (d, J = 7.7 Hz, 1 H), 4.49-4.34 (m, 1 H), 3.68-3.57 (m, 1 H), 3.40-3.31 (m, 2 H) , 3.23-3.11 (m, 1 H), 3.07-2.96 (m, 1 H), 2.55-2.49 (m, 4 H), 2.45-2.31 (m, 2 H), 2.23 (s, 3 H), 2.15 -1.98 (m, 2 H), 1.60-1.47 (m, 2 H), 1.39-1.25 (m, 2 H), 1.20-1.13 (m, 1 H), 0.92-0.88 (m, 6 H).

Compound 47 ((2S) -2-hydroxy-3-methyl-N-[(3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-yl] butaneamide) :. From 3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-amine and (2S) -2-hydroxy-3-methibutanoic acid, by prep-HPLC under the following conditions: Purified: Column, XBridge Shield Prep C18 OBD Column, 150 mm, 5 um; Mobile Phase, Acetonitrile in Water (containing 10 mmol / L NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 35% to 7 min 45% gradient; detector, UV 254 nm (20 mg, 24%, orange solid). HPLC: 99.6% purity, RT = 1.40 min. MS: m / z = 342.4 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, methanol-d _4, ppm) δ 8.85-8.77 (m, 1 H), 8.71-8.61 (m, 1 H), 7.53-7.42 (m, 2 H), 7.00 (d, J) = 7.8 Hz, 1 H), 4.70-4.58 (m, 1 H), 3.94-3.86 (m, 1 H), 3.80-3.68 (m, 1 H), 3.53-3.40 (m, 1 H), 3.32- 3.16 (m, 2 H), 2.76-2.60 (m, 4 H), 2.22-2.05 (m, 1 H), 1.10 (d, J = 7.0 Hz, 3 H), 1.03 (d, J = 7.0 Hz, 3 H), 0.92 (d, J = 6.8 Hz, 3 H).

Compound 48 ((2R) -2-hydroxy-3-methyl-N-[(3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-yl] butaneamide) :. From 3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-amine and (2R) -2-hydroxy-3-methylbutanoic acid under the following conditions on prep-HPLC. Purified: Column, XBridge Shield Prep C18 OBD Column, 150 mm, 5 um; Mobile Phase, Acetonitrile in Water (containing 10 mmol / L NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 35% to 7 min 45% gradient; detector, UV 254 nm (23 mg, 29%, orange solid). HPLC: 99.7% purity, RT = 1.39 min. MS: m / z = 342.4 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 8.85-8.77 (m, 1 H), 8.70-8.60 (m, 1 H), 7.52-7.41 (m, 2 H), 7.01 (d, J) = 7.8 Hz, 1 H), 4.69-4.56 (m, 1 H), 3.94 (d, J = 3.6 Hz, 1 H), 3.79-3.67 (m, 1 H), 3.53-3.41 (m, 1 H) , 3.31-3.15 (m, 2 H), 2.77-2.62 (m, 4 H), 2.18-2.00 (m, 1 H), 1.10 (d, J = 7.0 Hz, 3 H), 1.01 (d, J = 6.9 Hz, 3 H), 0.84 (d, J = 6.8 Hz, 3 H).
Example 15: Compounds 35 and 36 (N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] -2-[(3S) -1-methyl Piperidine-3-yl] acetamide and N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] -2-[(3R) -1-methyl Synthesis of piperidine-3-yl] acetamide)

N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] -2-[(3S) -1-methylpiperidin-3-yl] acetamide and N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] -2-[(3R) -1-methylpiperidin-3-yl] acetamide: 2- (1) in a solution of (3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-amine (49 mg, 0.20 mmol) in N, N-dimethylformamide (3 mL). -Methylpyrrolidine-3-yl) acetamide (46 mg, 0.30 mmol), HATU (120 mg, 0.30 mmol) and DIEA (126 mg, 0.98 mmol) were added at room temperature. The resulting solution was stirred for 14 hours at room temperature. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was first purified by prep-HPLC under the following conditions: column, XBride Prep C18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water (10 mmol). / L NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 20% -57% gradient at 7 min; detector, UV 254 nm. Two diastereomers were then obtained by separation on chiral prep-HPLC under the following conditions: column, CHIRALPAK IG-3, 0.46x10 cm, 3 um; mobile phase, hexane in 80% uniform concentration EtOH at 30 min (0). .Contains 1% DEA); Detector, UV 254 nm.

Isomer 1: (15 mg, 19%, red solid) HPLC: 99.8% purity, RT = 1.31 min. MS: m / z = 381.2 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 8.84-8.75 (m, 1 H), 8.72-8.62 (m, 1 H), 7.50-7.39 (m, 2 H), 6.96 (d, J) = 7.8 Hz, 1 H), 4.68-4.56 (m, 1 H), 3.81-3.69 (m, 1 H), 3.51-3.39 (m, 1 H), 3.30-3.09 (m, 4 H), 2.72- 2.51 (m, 8 H), 2.51-2.37 (m, 1 H), 2.31-2.09 (m, 3 H), 1.91-1.65 (m, 3 H), 1.24-1.10 (m, 1 H), 1.07 ( d, J = 6.9 Hz, 3 H).

Isomer 2: (18 mg, 10%, yellow solid) HPLC: 99.5% purity, RT = 1.30 min. MS: m / z = 381.2 [M + H] ⁺ . ^{1 1} H NMR (300 MHz, methanol-d _4, ppm) δ 8.84-8.75 (m, 1 H), 8.73-8.63 (m, 1 H), 7.51-7.40 (m, 2 H), 6.96 (d, J) = 7.8 Hz, 1 H), 4.69-4.56 (m, 1 H), 3.82-3.70 (m, 1 H), 3.51-3.35 (m, 2 H), 3.38-3.31 (m, 1 H), 3.30- 3.21 (m, 1 H), 3.21-3.10 (m, 1 H), 2.83-2.69 (m, 4 H), 2.72-2.54 (m, 5 H), 2.38-2.21 (m, 3 H), 2.00- 1.83 (m, 2 H), 1.86-1.65 (m, 1 H), 1.31-1.13 (m, 1 H), 1.07 (d, J = 6.9 Hz, 3 H).

The following compounds were synthesized in a similar manner:

Compounds 37 and 38 (N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] -2-[(3S) -1-methylpyrrolidine-3) -Il] Acetamide and N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] -2-[(3R) -1-methylpyrrolidine-3 -Il] acetamide): From (3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-amine and 2- (1-methylpyrrolidin-3-yl) acetic acid, Purified by prep-HPLC under the conditions of: column, XBridge Prep C18 OBD column, 150 mm, 5 um; mobile phase, containing acetonitrile in water (10 mmol / L NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O). ), 20% -47% gradient at 8 min; detector, UV 254 nm. The two isomers were obtained by separation on chiral prep-HPLC under the following conditions: column, CHIRALPAK IG-3, 0.46x10 cm, 3 um; mobile phase, MtBE (0) in 70% uniform concentration EtOH at 30 min. .1% DEA content); detector, UV 254 nm. Isomer 1: (25 mg, 26%, red solid) HPLC: 97.7% purity, RT = 2.14 min. MS: m / z = 367.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d _6, ppm) δ 8.89-8.83 (m, 1 H), 8.60-8.48 (m, 1 H), 7.95 (d, J = 8.5 Hz, 1 H), 7.48- 7.40 (m, 2 H), 6.84 (d, J = 7.8 Hz, 1 H), 4.54-4.43 (m, 1 H), 3.74-3.65 (m, 1 H), 3.50-3.35 (m, 1 H) , 3.28-3.18 (m, 1 H), 3.13-3.02 (m, 1 H), 2.65-2.30 (m, 8 H), 2.27-2.05 (m, 6 H), 1.94-1.80 (m, 1 H) , 1.41-1.28 (m, 1 H), 0.95 (d, J = 6.9 Hz, 3 H). Isomer 2: (25 mg, 26%, yellow solid) HPLC: 95.2% purity, RT = 2.16 min. MS: m / z = 367.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d _6, ppm) δ 8.89-8.83 (m, 1 H), 8.60-8.53 (m, 1 H), 7.96 (d, J = 8.5 Hz, 1 H), 7.48- 7.40 (m, 2 H), 6.84 (d, J = 7.8 Hz, 1 H), 4.54-4.43 (m, 1 H), 3.74-3.65 (m, 1 H), 3.44-3.35 (m, 1 H) , 3.28-3.19 (m, 1 H), 3.12-3.04 (m, 1 H), 2.62-2.57 (m, 3 H), 2.57-2.50 (m, 1 H), 2.49-2.37 (m, 4 H) , 2.20 (d, J = 9.5 Hz, 5 H), 2.15-2.06 (m, 1 H), 1.97-1.83 (m, 1 H), 1.44-1.31 (m, 1 H), 0.95 (d, J = 6.8 Hz, 3 H).

Compounds 45 and 46 ((2S) -2-cyclopropyl-2-hydroxy-N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] acetamide And (2R) -2-cyclopropyl-2-hydroxy-N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] acetamide): (3R) , 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-amine and 2-cyclopropyl-2-hydroxyacetoamide were purified by prep-HPLC under the following conditions: Column, XBridge RP18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water (containing 10 mmol / L NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 20% -50% gradient at 7 min; detector , UV 254 nm. The two diastereomers were obtained by separation on chiral prep-HPLC under the following conditions: column, CHIRALPAK IA-3, 0.46x5 cm, 3 um; mobile phase, hexane in EtOH at 70% uniform concentration at 15 min. (Contains 0.1% DEA); Detector, UV 254 nm. Isomer 1: (25 mg, 22%, red solid) HPLC: 97.6% purity, RT = 1.26 min. MS: m / z = 340.3 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 9.18-9.08 (m, 1 H), 8.92-8.83 (m, 1 H), 7.82-7.61 (m, 2 H), 7.04 (d, J) = 8.1 Hz, 1 H), 4.68-4.56 (m, 1 H), 3.93-3.81 (m, 1 H), 3.67-3.54 (m, 2 H), 3.46-3.31 (m, 2 H), 2.77- 2.61 (m, 4 H), 1.11-1.04 (m, 4 H), 0.56-0.29 (m, 4 H). Isomer 2: (25 mg, 22%, red solid) HPLC: 98.1% purity, RT = 1.26 min. MS: m / z = 340.4 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 8.87-8.74 (m, 2 H), 7.59-7.48 (m, 2 H), 7.02 (d, J = 7.9 Hz, 1 H), 4.70- 4.58 (m, 1 H), 3.83-3.72 (m, 1 H), 3.74-3.65 (m, 1 H), 3.57-3.44 (m, 1 H), 3.32-3.20 (m, 2 H), 2.77- 2.62 (m, 4 H), 1.26-1.05 (m, 4 H), 0.60-0.37 (m, 4 H).
Example 16: Compound 41 (2- (4-fluoropiperidin-4-yl) -N-[(3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-yl] Synthesis of acetamide)

tert-Butyl 4-fluoro-4-([[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] carbamoyl] methyl) piperidine-1-carboxylate : (3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) piperidine-3-amine (59 mg, 0.24 mmol) in N, N-dimethylformamide (3 mL) solution 2- [ 1-[(tert-Butoxy) carbonyl] -4-fluoropiperidine-4-yl] acetic acid (101 mg, 0.39 mmol), HATU (138 mg, 0.36 mmol) and DIEA (153 mg, 1.18 mmol) at room temperature. Added. The resulting solution was stirred at room temperature for 16 hours. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBride Shield Prep C18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water (10 mmol /). Contains L NH ₄ HCO ₃ and 0.1% NH _3. H ₂ O), 32% -35% gradient at 7 min; detector, UV 254 nm. tert-Butyl 4-fluoro-4-([[(3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-yl] carbamoyl] methyl) piperidine-1-carboxylate Was obtained as a yellow solid (19 mg, 16%). MS: m / z = 485.3 [M + H] ⁺ .

2- (4-Fluoropiperidin-4-yl) -N-[(3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-yl] acetamide: tert-butyl 4 -Fluoro-4-([[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] carbamoyl] methyl) piperidine-1-carboxylate (17 mg, 0) A hydrochloric acid solution (4 M in dioxane, 1 mL, 4 mmol) was added to a solution of 0.05 mmol) in methanol (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBridge Shield Prep C18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water (10 mmol). / L _NH 4 containing HCO ₃ and _{0.1% NH 3 .H 2 O)} , 32% ~35% in 7min gradient; detector, UV 254 nm. 2- (4-Fluoropiperidin-4-yl) -N-[(3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-yl] acetamide in a pale yellow solid ( Obtained as 10 mg, 71%).

Compound 41: HPLC: 96.3% purity, RT = 0.85 min. MS: m / z = 385.2 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 8.84-8.76 (m, 1 H), 8.74-8.63 (m, 1 H), 7.53-7.40 (m, 2 H), 7.01-6.92 (m) , 1 H), 4.69-4.57 (m, 1 H), 3.82-3.70 (m, 1 H), 3.52-3.39 (m, 1 H), 3.36-3.00 (m, 6 H), 2.82-2.56 (m) , 6 H), 2.23-1.85 (m, 4 H), 1.08 (d, J = 7.0 Hz, 3 H).
Example 17: Compound 42 (2- (4-fluoro-1-methylpiperidin-4-yl) -N-[(3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine- 3-Il] acetamide) synthesis

2- (4-Fluoro-1-methylpiperidine-4-yl) -N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] acetamide: 2- (4-Fluoropiperidin-4-yl) -N-[(3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-yl] acetamide (176 mg, 0. (CH ₂ O) _n (423 mg, 4.69 mmol) and NaOAc (790 mg, 9.64 mmol) were added to a 46 mmol) MeOH (30 mL) solution at room temperature. The resulting mixture was stirred at room temperature for 2 hours, and then NaBH ₄ (275 mg, 7.27 mmol) was added in portions. The reaction mixture was further stirred at room temperature for 16 hours. When the reaction was completed, it was stopped by the addition of water (20 mL). The resulting mixture was extracted with DCM (50 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBride Shield Prep C18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water (10 mmol / L NH ₄ HCO ₃ and Contains 0.1% NH ₃ .H ₂ O), 30% -43% gradient at 7 min; detector, UV 254 nm. 2- (4-Fluoro-1-methylpiperidin-4-yl) -N-[(3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-yl] acetamide Obtained as a yellow solid (90 mg, 49%).

Compound 42: HPLC: 96.5% purity, RT = 7.86 min. MS: m / z = 399.4 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d _6, ppm) δ 8.89-8.83 (m, 1 H), 8.60-8.52 (m, 1 H), 8.03 (d, J = 8.5 Hz, 1 H), 7.48- 7.40 (m, 2 H), 6.84 (d, J = 7.8 Hz, 1 H), 4.55-4.43 (m, 1 H), 3.75-3.66 (m, 1 H), 3.45-3.36 (m, 1 H) , 3.28-3.19 (m, 1 H), 3.14-3.06 (m, 1 H), 2.62-2.42 (m, 8 H), 2.18-2.03 (m, 5 H), 1.91-1.68 (m, 4 H) , 0.97 (d, J = 6.8 Hz, 3 H).
Example 18: Compounds 43 and 44 (2-[(4S) -3,3-difluoro-1-methylpyrrolidine-4-yl] -N-[(3R, 4R) -4-methyl-1- (8-methyl) Kinolin-5-yl) pyrrolidine-3-yl] acetamide and 2-[(4R) -3,3-difluoro-1-methylpiperidin-4-yl] -N-[(3R, 4R) -4-methyl- Synthesis of 1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] acetamide)

tert-Butyl 3,3-difluoro-4-([[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] carbamoyl] methyl) piperidine-1- Carboxylate: 2 in a solution of (3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) piperidine-3-amine (121 mg, 0.50 mmol) in N, N-dimethylformamide (3 mL). -{1-[(tert-butoxy) carbonyl] -3,3-difluoropiperidine-4-yl} acetic acid (363 mg, 1.30 mmol), HATU (342 mg, 0.90 mmol) and DIEA (380 mg, 2.94 mmol) Was added at room temperature. The resulting solution was stirred at room temperature for 2 hours. When the reaction was completed, it was stopped by the addition of water (20 mL). The resulting mixture was extracted with DCM (60 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . Solvent Removed under reduced pressure tert-butyl 3,3-difluoro-4-([[(3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-yl] carbamoyl] methyl] ) Piperidine-1-carboxylate was produced as yellow oil (300 mg, crude product). MS: m / z = 503.4 [M + H] ⁺ .

2- (3,3-difluoropiperidine-4-yl) -N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] acetamide: tert- Butyl 3,3-difluoro-4-([[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine-3-yl] carbamoyl] methyl) piperidine-1-carboxylate To a solution of (300 mg, crude product) in methanol (4 mL) was added a hydrochloric acid solution (4 M in dioxane, 4 mL, 16 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. When the reaction was complete, the pH value of the reaction mixture was adjusted to 7-8 with saturated NaHCO ₃ solution. The resulting mixture was extracted with ethyl acetate (50 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent is removed under reduced pressure and 2- (3,3-difluoropiperidine-4-yl) -N-[(3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) pyrrolidine-3-3 Il] Acetamide was produced as a yellow oil (330 mg, crude). MS: m / z = 403.4 [M + H] ⁺ .

2-[(4S) -3,3-difluoro-1-methylpiperidine-4-yl] -N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-5-yl) pyrrolidine- 3-Il] acetamide and 2-[(4R) -3,3-difluoro-1-methylpiperidin-4-yl] -N-[(3R, 4R) -4-methyl-1- (8-methylquinolin-) 5-yl) Pyrrolidine-3-yl] Acetamide: 2- (3,3-difluoropiperidine-4-yl) -N-[(3R, 4R) -4-methyl-1- (8-methylquinoline-5-yl) Il) Pyrrolidine-3-yl] Acetamide (330 mg, crude) in a solution of methanol (50 mL) with (CH ₂ O) _n (684 mg, 7.59 mmol) and NaOAC (1.27 g, 15.52 mmol) at room temperature. Added. The resulting mixture was stirred at room temperature for 2 hours, and then NaBH ₄ (444 mg, 11.73 mmol) was added in portions. The reaction mixture was further stirred at room temperature for 16 hours. When the reaction was completed, the reaction was stopped by adding water (20 mL). The resulting mixture was extracted with DCM (50 mLx3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and and the residue was first purified by prep-HPLC under the following conditions: column, XBride Prep C18 OBD column, 150 mm, 5 um; mobile phase, acetonitrile in water (10 mmol / L NH ₄ HCO ₃ and 0.1% _NH 3 .H ₂ O-containing), 27% to 46% gradient in 7min; detector, UV 254 nm. Two diastereomers were then obtained by separation on chiral prep-HPLC under the following conditions: column, Repeat ADH, 0.46x10 cm, 3 um; mobile phase, hexane in 70% uniform concentration EtOH at 30 min (0. Contains 1% DEA); detector, UV 254 nm.

Isomer 1: (15 mg, 7% in 3 steps, grayish white solid) HPLC: 97.9% purity, RT = 2.77 min. MS: m / z = 209.1 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 8.83-8.75 (m, 1 H), 8.73-8.59 (m, 1 H), 7.50-7.39 (m, 2 H), 6.96 (d, J) = 7.8 Hz, 1 H), 4.68-4.56 (m, 1 H), 3.80-3.68 (m, 1 H), 3.56-3.39 (m, 1 H), 3.29-2.97 (m, 3 H), 2.87- 2.54 (m, 6 H), 2.40-2.18 (m, 6 H), 2.16-2.01 (m, 1 H), 1.81-1.69 (m, 1 H), 1.61-1.42 (m, 1 H), 1.06 ( d, J = 6.9 Hz, 3 H).

Isomer 2: (15 mg, 7% in 3 steps, grayish white solid) HPLC: 98.6% purity, RT = 2.70 min. MS: m / z = 209.0 [M + H] ⁺ . ¹ H NMR (300 MHz, methanol-d _4, ppm) δ 8.84-8.75 (m, 1 H), 8.74-8.64 (m, 1 H), 7.51-7.40 (m, 2 H), 6.97 (d, J) = 7.8 Hz, 1 H), 4.70-4.54 (m, 1 H), 3.79-3.67 (m, 1 H), 3.52-3.33 (m, 1 H), 3.31-2.98 (m, 3 H), 2.91- 2.81 (m, 1 H), 2.77-2.55 (m, 5 H), 2.41-2.20 (m, 6 H), 2.20-2.06 (m, 1 H), 1.91-1.80 (m, 1 H), 1.66- 1.52 (m, 1 H), 1.06 (d, J = 6.9 Hz, 3 H).
Example 19: Compounds 49 and 50 ((3S, 4R) -4-fluoro-1- (8-trifluoromethyl-quinoline-5-yl) -pyrrolidine-3-ylamine and (3R, 4S) -4-fluoro- Synthesis of 1- (8-trifluoromethyl-quinoline-5-yl) -pyrrolidine-3-ylamine)

[Cis-4-fluoro-1- (8-trifluoromethyl-quinoline-5-yl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester: 5-bromo-8- (trifluoromethyl) quinoline ( In a solution of 400 mg; 1.45 mmol) in tBuOH (9.0 mL), cis- (3-boc-amino) -4-fluoropyrrolidine (355 mg; 1.74 mmol), chloro (2-dicyclohexylphosphino-2', 6'-Di-i-propoxy-1,1'-biphenyl) [2- (2-aminoethylphenyl)] palladium (ii), methyl-t-butyl ether adduct (59.2 mg; 0.072 mmol), 2-dicyclohexyl Phenyl-2', 6'-di-i-propoxy-1,1'-biphenyl (33.8 mg; 0.072 mmol) and cesium carbonate (944 mg; 2.90 mmol) were added. The resulting mixture was sprayed with nitrogen for 10 minutes and irradiated with 8 h microwaves at 85 ^o C. The reaction mixture was concentrated under reduced pressure, suspended in DCM (20 mL), sonicated for 30 seconds and filtered over Celite. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc (10% -80% gradient) in hexanes to [cis-4-fluoro-1- (8-trifluoromethyl-quinolin-5). -Il) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester was produced as a solid (507 mg; 88%) on a light brown glass. MS: m / z = 400 [M + H] ⁺ .

(3S, 4R) -4-fluoro-1- (8-trifluoromethyl-quinoline-5-yl) -pyrrolidin-3-ylamine and (3R, 4S) -4-fluoro-1- (8-trifluoromethyl) -Quinoline-5-yl) -Pyrrolidine-3-ylamine: [cis-4-fluoro-1- (8-trifluoromethyl-quinoline-5-yl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester A hydrochloric acid solution (4M in dioxane, 9 mL, 36 mmol) was added to a solution of (485 mg; 1.21 mmol) in methanol (12 mL) at room temperature. The resulting mixture was stirred at room temperature overnight. When the reaction was complete, ether (40 mL) was added to the orange solution and the yellow suspension (liquid) was stirred at room temperature for 1 h. The solid was filtered and dissolved in 5N potassium hydroxide solution. The mixture was extracted with ethyl acetate and the combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Two enantiomers were obtained by separation on chiral prep-HPLC under the following conditions: column, Lux cellulose-2, 250x21.20 mm, 5 um; mobile phase, containing 0.5% DMEA at a uniform concentration of 30% in 11 min. EtOH; detector, UV 254 nm.

Isomer 1: (86 mg, 23%, light brown solid) HPLC: 98.9% purity, RT = 1.78 min. MS: m / z = 300 [M + H] ⁺ . ¹ H NMR (400 MHz, chloroform-d, ppm) d 8.86 (d, J = 1.7 Hz, 1H), 8.64 (d, J = 5.6 Hz, 1H), 8.60 (d, J = 1.7 Hz, 1H), 6.49 (d, J = 5.7 Hz, 1H), 6.41 (s, 1H), 4.29-4.14 (m, 2H), 4.08 (dt, J = 12.2, 7.3 Hz, 1H), 3.91 (q, J = 9.2, 8.7 Hz, 1H), 3.40-3.26 (m, 2H), 3.06 (p, J = 7.6 Hz, 1H), 2.56 (t, J = 6.0 Hz, 2H), 2.52 (q, J = 7.1 Hz, 4H) , 2.41-2.24 (m, 2H), 0.99 (t, J = 7.1 Hz, 6H).

Isomer 2: (104 mg, 29%, cream solid) HPLC:> 99.9% purity, RT = 1.75 min. MS: m / z = 300 [M + H] ⁺ . ¹ H NMR (400 MHz, chloroform-d, ppm) d 8.99 (dd, J = 4.1, 1.7 Hz, 1H), 8.47 (dd, J = 8.7, 1.7 Hz, 1H), 7.90 (dd, J = 8.4, 0.8 Hz, 1H), 7.37 (dd, J = 8.7, 4.1 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 5.05 (dt, J = 54.5, 3.4 Hz, 1H), 4.05 (ddd, J = 37.9, 12.3, 3.6 Hz, 1H), 3.79 --3.54 (m, 4H), 1.52 (s, 2H).
Example 20: Synthesis of compound 51 ((3R, 4R) -4-methyl-1- (8-methyl- [1,7] naphthylidine-5-yl) -pyrrolidine-3-ylamine hydrochloride)

[(3R, 4R) -4-methyl-1- (8-methyl- [1,7] naphthylidine-5-yl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester: 5-bromo-8- (3R, 4R) -3- (boc-amino) -4-methylpyrrolidin (104 mg; 0.49 mmol) in a tBuOH (1.5 mL) solution of methyl- [1,7] naphthylidine (100 mg; 0.45 mmol)) , Chloro (2-dicyclohexylphosphino-2', 6'-di-i-propoxy-1,1'-biphenyl) [2- (2-aminoethylphenyl)] palladium (ii), methyl-t-butyl ether Additives (18.3 mg; 0.02 mmol), 2-dicyclohexylphosphino-2', 6'-di-i-propoxy-1,1'-biphenyl (10.5 mg; 0.02 mmol), cesium carbonate (292 mg) 0.90 mmol) was added. The resulting mixture was sprayed with nitrogen for 10 minutes and irradiated with microwaves at 100 ^o C for 8 h. The reaction mixture is concentrated under reduced pressure and the residue is purified by flash chromatography eluting with EtOAc (20% -80% gradient) in hexane [(3R, 4R) -4-methyl-1- (8-methyl). -[1,7] Naftyridin-5-yl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester was produced as a pale yellow solid (70 mg; 46%). MS: m / z = 343 [M + H] ⁺ .

(3R, 4R) -4-Methyl-1- (8-Methyl- [1,7] Naftyridin-5-yl) -Pyrrolidine-3-ylamine Hydrochloride: [(3R, 4R) -4-Methyl-1- (8-Methyl- [1,7] diazanaphthalene-5-yl) -pyrrolidin-3-yl] -carbamic acid tert-butyl ester (120 mg, 0.35 mmol) in methanol (3 mL) in hydrochloric acid solution (4M in dioxane) , 1.3 mL, 5.3 mmol) was added at room temperature. The resulting mixture was stirred overnight at room temperature. When the reaction is complete, the mixture is concentrated and dried and (3R, 4R) -4-methyl-1- (8-methyl- [1,7] naphthylidine-5-yl) -pyrrolidine-3-ylamine hydrochloride Was produced as a yellow amorphous solid (110 mg; 97%).

Compound 51: HPLC: 98.9% purity, RT = 0.93 min. MS: m / z = 243 [M + H] ⁺ .
Example 21: Compound 52 (N-[(3R, 4R) -4-methyl-1- (8-methyl- [1,7] naphthylidine-5-yl) -pyrrolidine-3-yl] -2- (1-) Synthesis of methyl-piperidin-4-yl) -acetamide)

N-[(3R, 4R) -4-methyl-1- (8-methyl- [1,7] naphthylidine-5-yl) -pyrrolidine-3-yl] -2- (1-methyl-piperidine-4-yl) Il) -acetamide: (3R, 4R) -4-methyl-1- (8-methyl- [1,7] naphthylidine-5-yl) -pyrrolidine-3-ylamine hydrochloride 30 mg, 0.1 mmol) N, 2- (1-Methylpiperidin-4-yl) acetamide (16.5 mg, 0.105 mmol), DIEA (63 mL, 0.948 mmol) and (benzotriazole-1-yloxy) tris in a solution of N-dimethylformamide (1 mL) (Dimethylamino) phosphonium hexafluorophosphate (51 mg, 0.114 mmol) was added. The resulting solution was stirred at room temperature for 1 hour. When the reaction was complete, the solvent was removed under reduced pressure and the residue was purified by prep-HPLC under the following conditions: column, XBride Prep C18 OBD 10 mm, column, 30x250 mm; mobile phase, acetonitrile in water (containing 0.1% NH4OH). ), 10% -60% gradient at 15 min; detector, UV 254 nm. N-[(3R, 4R) -4-methyl-1- (8-methyl- [1,7] naphthylidine-5-yl) -pyrrolidine-3-yl] -2- (1-methyl-piperidin-4-yl) Il) -acetamide was obtained as a white amorphous solid (32 mg, 88%).

Compound 52: HPLC:> 99% purity, RT = 1.30 min. MS: m / z = 382 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) d 8.96 (dd, J = 4.1, 1.6 Hz, 1H), 8.60 (dd, J = 8.7, 1.6 Hz, 1H), 7.91 (d, J = 8.4 Hz) , 1H), 7.86 (s, 1H), 7.66 (dd, J = 8.7, 4.1 Hz, 1H), 4.48 (dtd, J = 9.2, 6.0, 3.4 Hz, 1H), 3.85 (dd, J = 9.9, 6.0 Hz, 1H), 3.51 (dd, J = 9.1, 7.3 Hz, 1H), 3.36 (d, J = 8.9 Hz, 1H), 3.20 (dd, J = 9.9, 3.4 Hz, 1H), 2.81 (s, 3H) ), 2.73 --2.61 (m, 2H), 2.49 --2.43 (m, 1H), 2.10 (s, 3H), 2.08 --1.99 (m, 2H), 1.77 (tdd, J = 11.3, 5.8, 2.4 Hz, 2H) ), 1.65 --1.45 (m, 3H), 1.20 --1.05 (m, 2H), 0.97 (d, J = 6.8 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 53 (2- (1-methyl-azetidine-3-yl) -N-[(3R, 4R) -4-methyl-1- (8-methyl- [1,7] naphthididine-5-yl) -pyrrolidine -3-yl] -acetoamide): 8-[(3R, 4R) -3-amino-4-methylpyrrolidine-1-yl] quinoxaline-5-carbonitrile and (1-methyl-azetidine-3-yl)- Purified from acetate by prep-HPLC under the following conditions: column, XBridge Prep C18 OBD 10 μm, column, 30x250 mm; mobile phase, acetonitrile in water (containing 0.1% NH4OH), 10% -60% in 15 min. Gradient; detector, UV 254 nm (29 mg, 86%, white amorphous solid). HPLC:> 99% purity, RT = 1.24 min. MS: m / z = 354 [M + H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) d 8.97 (dd, J = 4.1, 1.5 Hz, 1H), 8.61 (dd, J = 8.7, 1.7 Hz, 1H), 7.97 (d, J = 8.5 Hz) , 1H), 7.87 (s, 1H), 7.67 (dd, J = 8.7, 4.1 Hz, 1H), 4.46 (dtd, J = 9.3, 6.0, 3.4 Hz, 1H), 3.85 (dd, J = 9.9, 6.0 Hz, 1H), 3.51 (dd, J = 9.1, 7.3 Hz, 1H), 3.38 --3.32 (m, 1H), 3.28 --3.15 (m, 3H), 2.82 (s, 3H), 2.78 --2.68 (m, 2H), 2.61 --2.55 (m, 1H), 2.48 --2.31 (m, 3H), 2.14 (s, 3H), 0.95 (d, J = 6.9 Hz, 3H).
Example 22: Synthesis of compound 54 (1-pyrido [2,3-b] pyrazine-8-yl-pyrrolidin-3-carboxylic acid (2-diethylamino-ethyl) -amide)

3- (2-Diethylamino-ethylcarbamoyl) -pyrrolidin-1-carboxylic acid tert-butyl ester: 1-voca-pyrrolidin-3-carboxylic acid (1.0 g, 4.65 mmol) anhydrous dichloromethane (25.0 mL) solution A 50% solution of N, N-diethylethylenediamine (653 μl, 4.65 mmol), DIEA (4.0 ml, 23.2 mmol) and propylphosphonic acid anhydride (8.2 mL, 13.9 mmol) in ethyl acetate was added. .. The resulting solution was stirred at room temperature for 1 h30 hours (1 h30 hours). When the reaction was complete, it was diluted with dichloromethane (70 mL), extracted with saturated sodium bicarbonate solution (3x50 mL) and washed with brine (50 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue is eluted with EtOAC (10% -60% gradient) in hexanes using an NH2-bound silica column by flash chromatography. Purification was performed to produce 3- (2-diethylamino-ethylcarbamoyl) -pyrrolidin-1-carboxylic acid tert-butyl ester as a colorless oil (1.21 g, 83%). MS: m / z = 314 [M + H] ⁺ .

Pyrrolidine-3-carboxylic acid (2-diethylamino-ethyl) -amide hydrochloride: 3- (2-diethylamino-ethylcarbamoyl) -pyrrolidin-1-carboxylic acid tert-butyl ester (1.2 g; 3.73 mmol) in methanol A hydrochloric acid solution (4M in dioxane, 28 mL, 112 mmol) was added to the (30 mL) solution at room temperature. The resulting mixture was stirred at room temperature overnight. When the reaction was complete, the mixture was concentrated under reduced pressure, the residue was dissolved in isopropanol (20 mL), acetonitrile (50 mL) and ether (10 mL) were added, and the colorless solution was stirred at room temperature overnight. The white suspension was filtered and the white solid was dried under vacuum to produce pyrrolidine-3-carboxylic acid (2-diethylamino-ethyl) -amide hydrochloride as a white solid (581 mg, 62%). MS: m / z = 214 [M + H] ⁺ .

1-pyrido [2,3-b] pyrazine-8-yl-pyrrolidin-3-carboxylic acid (2-diethylamino-ethyl) -amide: 8-chloro-pyrido [2,3-b] pyrazine (60 mg, 0. 362 mmol), pyrrolidine-3-carboxylic acid (2-diethylamino-ethyl) -amide hydrochloride (136 mg, 0.544 mmol) and DIEA (316 μl, 1.81 mmol) in anhydrous ethanol (3 mL) solution at 100 ^o C for 3 h micron. The waves were irradiated. When the reaction is complete, the solvent is removed under reduced pressure and the residue is purified by flash chromatography eluting with methanol (0% -7% gradient) in dichloromethane using an NH2-linked silica column and 1-pyrido [. 2,3-b] Pyrazine-8-yl-pyrrolidin-3-carboxylic acid (2-diethylamino-ethyl) -amide was produced as a yellow solid (108 mg, 85%).

Compound 54: HPLC: 97.3% purity, RT = 1.00 min. MS: m / z = 343 [M + H] ⁺ . ¹ H NMR (400 MHz, chloroform-d, ppm) d 8.86 (d, J = 1.7 Hz, 1H), 8.64 (d, J = 5.6 Hz, 1H), 8.60 (d, J = 1.7 Hz, 1H), 6.49 (d, J = 5.7 Hz, 1H), 6.41 (s, 1H), 4.29-4.14 (m, 2H), 4.08 (dt, J = 12.2, 7.3 Hz, 1H), 3.91 (q, J = 9.2, 8.7 Hz, 1H), 3.40-3.26 (m, 2H), 3.06 (p, J = 7.6 Hz, 1H), 2.56 (t, J = 6.0 Hz, 2H), 2.52 (q, J = 7.1 Hz, 4H) , 2.41-2.24 (m, 2H), 0.99 (t, J = 7.1 Hz, 6H).
Example 23: Compound 55 ([1- (1,2-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -pyrrolidine-3-ylmethyl]-(2-piperidine-1-yl-ethyl) ) -Amine) synthesis

3-[(2-Piperidin-1-yl-ethylamino) -methyl] -pyrrolidine-1-carboxylic acid tert-butyl ester: 3-formyl-pyrrolidin-1-carboxylic acid tert-butyl ester (200 mg, 0.98 mmol) ) And 2-piperidin-1-yl-ethylamine (126 mg, 0.98 mmol) in a mixture of methanol (0.40 mL) and 1,2-dichloroethane (1.60 mL) with acetic acid (66 mg, 1.08 mmol). Addition and the reaction mixture were stirred at room temperature for 1 h. Sodium triacetoxyborohydride (329 mg, 1.48 mmol) was then added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then poured into cold ice water (10 mL) and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give 3-[(2-piperidin-1-yl-ethylamino) -methyl] -pyrrolidine-1-carboxylic acid tert-butyl ester pale yellow. Produced as a gum-like substance (150 mg, 38%). MS: m / z = 312.3 [M + H] ⁺ .

3-{[benzyloxycarbonyl- (2-piperidin-1-yl-ethyl) -amino] -methyl} -pyrrolidin-1-carboxylic acid tert-butyl ester: 3-[(2-piperidin-1-yl-ethyl) Amino) -methyl] -pyrrolidin-1-carboxylic acid tert-butyl ester (150 mg, 0.38 mmol) in a solution of THF (1.2 mL) and water (0.3 mL) potassium hydroxide (45 mg, 1.13 mmol) And 50% (0.12 mL, 0.41 mmol) of benzyl chloroformate in toluene was added. The reaction mixture was stirred at room temperature for 24 hours, poured into ice-cold water (10 mL) and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to tert 3-{[benzyloxycarbonyl- (2-piperidin-1-yl-ethyl) -amino] -methyl} -pyrrolidin-1-carboxylic acid tert. -Butyl ester was produced as a pale yellow gum-like substance (150 mg, 47%). MS: m / z = 446.3 [M + H] ⁺ .

(2-Piperidine-1-yl-Ethyl) -Pyrrolidine-3-ylmethyl-Carbamate benzyl Ester Trifluoroacetate: 3-{[benzyloxycarbonyl- (2-Piperidine-1-yl-ethyl) -amino]- Trifluoroacetic acid (0.75 mL) in a solution of methyl} -pyrrolidin-1-carboxylic acid tert-butyl ester (150 mg, 0.18 mmol) at 0 ^o C in dichloromethane (0.75 mL) for a period of 30 minutes. Dropped over. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was then concentrated under reduced pressure and azeotroped with toluene to add (2-piperidine-1-yl-ethyl) -pyrrolidine-3-ylmethyl-carbamic acid benzyl ester trifluoroacetate to a brown gum (80 mg,). 57%). MS: m / z = 346.3 [M + H] ⁺ .

[1- (1,2-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -pyrrolidine-3-ylmethyl]-(2-piperidin-1-yl-ethyl) -carbamic acid benzyl ester : 4-Bromo-1,2-dimethyl-1H-pyrrolo [2,3-b] pyridine (200 mg, 0.88 mmol) and (2-piperidine-1-yl-ethyl) -pyrrolidine-3-ylmethyl-carbamic acid Potassium tert-butoxide (307 mg, 2.65 mmol), 2,2'-bis-diphenylphosphanyl- [1,1'] binaphthalenyl in a toluene (2 mL) solution of benzyl ester trifluoroacetate (847 mg, 1.06 mmol). (56 mg, 0.09 mmol) was added. The reaction mixture was degassed for 30 minutes before adding tris (dibenzylideneacetone) dipalladium (0) (42 mg, 0.04 mmol). The reaction mixture was heated in a sealed tube at 100 ^o C for 24 hours, poured into ice-cold water (30 mL) and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to [1- (1,2-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -pyrrolidine-3-ylmethyl. ]-(2-Piperidine-1-yl-ethyl) -carbamic acid benzyl ester was produced as a black gum-like substance (220 mg, 15%). MS: m / z = 490.2 [M + H] ⁺ .

[1- (1,2-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -pyrrolidine-3-ylmethyl]-(2-piperidin-1-yl-ethyl) -amine: [1 -(1,2-dimethyl-1H-pyrrolo [2,3-b] pyridin-4-yl) -pyrrolidine-3-ylmethyl]-(2-piperidine-1-yl-ethyl) -carbamic acid benzyl ester (200 mg) , 0.12 mmol) dioxane (1 mL) solution was added with a 4M hydrochloric acid solution (0.15 mL, 0.60 mmol) in the dioxane. The resulting pink reaction mixture was heated at 65 ^o C for 5 hours and concentrated under reduced pressure. The resulting mixture was dissolved in water, basicized with aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to provide the crude product, which was purified by flash chromatography and [1- (1,2-dimethyl-1H-pyrrolidine] [2. 3-b] Pyridine-4-yl) -pyrrolidine-3-ylmethyl]-(2-piperidin-1-yl-ethyl) -amine was produced as a brown gum-like substance (10 mg, 23%).

Compound 55: HPLC: 97.3% purity, RT = 1.00 min. MS: m / z = 343 [M + H] ⁺ . ¹ H NMR (400 MHz, chloroform-d, ppm) d 8.86 (d, J = 1.7 Hz, 1H), 8.64 (d, J = 5.6 Hz, 1H), 8.60 (d, J = 1.7 Hz, 1H), 6.49 (d, J = 5.7 Hz, 1H), 6.41 (s, 1H), 4.29-4.14 (m, 2H), 4.08 (dt, J = 12.2, 7.3 Hz, 1H), 3.91 (q, J = 9.2, 8.7 Hz, 1H), 3.40-3.26 (m, 2H), 3.06 (p, J = 7.6 Hz, 1H), 2.56 (t, J = 6.0 Hz, 2H), 2.52 (q, J = 7.1 Hz, 4H) , 2.41-2.24 (m, 2H), 0.99 (t, J = 7.1 Hz, 6H).
Example 24: HEK TLR7 cell assay

5000 c / w TLR7 / NFKb HEK cells and 10% FCS-HI, 2 mM L-Glutamine, 1% Pen / in 30 uL phenol red-free DMEM (gibco # 31053) in 384 culture plates (Corning 3707). Strept was added. Cells were cultured at 37 ° C. and 10% carbon dioxide for 24 hours. Control, standard, and compound 3uL were dispensed into wells, cultured for 30 minutes, and then added 3uL of R848 (10uM final concentration) agonist in 20 mM Hepes. Incubated for 5 hours and then left at room temperature for 15 minutes. 10 uL of Steady-Glo substrate reagent was added and the assay plate was vibrated at 1500 rpm for 5 minutes. The assay plate was allowed to sit at room temperature for 30 minutes and then the plate was read on EnVision.
Example 25: HEK TLR8 Cell Assay

5000 c / w TLR7 / NFKb HEK cells in 30 uL phenol red-free DMEM (gibco # 31053) in 384 culture plates (Corning 3707) and 10% FCS-HI, 2 mM L-Glutamine, 1% Pen / Strept was added. Cells were cultured at 37 ° C. and 10% carbon dioxide for 24 h. Control, standard, and compound 3uL were dispensed into wells, cultured for 30 minutes, and then added 3uL of R848 (30uM final concentration) agonist in 20 mM Hepes. Incubated for 5 hours and then left at room temperature for 15 minutes. 10 uL of Steady-Glo substrate reagent was added and the assay plate was vibrated at 1500 rpm for 5 minutes. The assay plate was allowed to sit at room temperature for 30 minutes and then the plate was read on EnVision.

The results are given in the table below.
A: IC ₅₀ <1uM
B: IC ₅₀ : 1uM-10uM
C: IC ₅₀ > 10uM
Table 2



Example 26 Pharmaceutical preparation

(A) Injection vial: A solution of 100 g of the active ingredient according to the present invention in water distilled twice and 5 g of disodium hydrogen phosphate was adjusted to pH 6.5 using 2N hydrochloric acid, and sterilized and filtered. Transfer into an injection vial, freeze dry under sterile conditions and seal under sterile conditions. Each injection vial contains 5 mg of active ingredient.

(B) Suppository: 20 g of a mixture of active ingredients according to the invention is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into a mold and cooled. Each suppository contains 20 mg of active ingredient.

(C) The solution: The solution, doubly distilled active ingredients according to the invention in water 1g of _{940ml, NaH 2 PO 4 · 2H} 2 O, Na 2 HPO 4 · 12H 2 O and 0 of 28.48g of 9.38g Prepared from 1 g of benzalkonium chloride. Adjust the pH to 6.8 to a maximum of 1 liter of solution and sterilize with radiation. This solution can be used in the form of eye drops.

(D) Ointment: 500 mg of the active ingredient according to the invention is mixed with 99.5 g of petrolatum under sterile conditions.

(E) Tablets: 1 kg of the active ingredient according to the invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate are compressed, and each tablet is 10 mg. The tablets are given in a conventional manner such that they contain the active ingredient.

(F) Coated Tablets: Tablets are compressed similar to Example E and subsequently coated in a conventional manner with coatings of sucrose, potato starch, talc, tragacanth and dyes.

(G) Capsules: 2 kg of the active ingredient according to the invention is introduced into the hard gelatin capsule in a conventional manner such that each capsule contains 20 mg of the active ingredient.

(H) Ampoule: 60 liters of a solution of the active ingredient according to the present invention in 1 kg of twice-distilled water is sterilized and filtered, transferred into an ampoule, lyophilized under sterilized conditions, and sealed under sterilized conditions. Each ampoule contains 10 mg of active ingredient.

(I) Inhalation spray: 14 g of the active ingredient according to the invention is dissolved in 10 liters of isotonic NaCl solution, and this solution is transferred into a commercially available spray container with a pump mechanism. The solution can be sprayed into the mouth or nose. A single spray shot (about 0.1 ml) corresponds to a dose of about 0.14 mg.

Although many aspects of the invention are described herein, it is clear that modifications to the basic examples may provide other aspects that utilize the compounds and methods of the invention. .. Therefore, it will be understood that the scope of the invention should be defined by the accompanying claims rather than by the particular embodiments represented by the examples.

Claims (20)

Formula I,
A compound represented by, or a pharmaceutically acceptable salt thereof,
During the ceremony:
Ring A is an aryl, or a heteroaryl having 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, and sulfur); each of them may be optionally substituted. ;
Ring B is a heteroaryl having 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, and sulfur); each of them may be optionally substituted;
R ¹ is -CH ₃ , -CF ₃ , or -CN;
Each R ² independently has -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C (O) R, -CO. ₂ R, -C (O) N (R) ₂ , -NRC (O) R, -NRC (O) N (R) ₂ , -NRSO ₂ R, or -N (R) ₂ ;
Each R ³ independently has -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C (O) R, -CO. ₂ R, -C (O) N (R) ₂ , -NRC (O) R, -NRC (O) N (R) ₂ , -NRSO ₂ R, or -N (R) ₂ ;
Each R ⁴ independently has -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C (O) R, -CO. ₂ R, -C (O) N (R) ₂ , -NRC (O) R, -NRC (O) N (R) ₂ , -NRC (O) OR, -NRSO ₂ R, or -N (R) ₂ ;
Each R ⁵ independently has -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C (O) R, -CO. ₂ R, -C (O) N (R) ₂ , -NRC (O) R, -NRC (O) N (R) ₂ , -NRSO ₂ R, or -N (R) ₂ ;
Each R is independently hydrogen, C _1-6 aliphatic, C _3-10 aryl, 3-8 member saturated or partially unsaturated carbocycles, 1-4 heteroatoms (independently, nitrogen). , Oxygen, or sulfur) with 3-7 members, or 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur) with 5-6 members Is a monocyclic heteroaryl ring; each of them may be optionally substituted; or two R groups on the same atom, together with the atom to which they are attached, C. _3- to 7-membered hetero with 3 to ₁₀ aryl, _3- to 8-membered saturated or partially unsaturated carbocycles, 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur) It forms a ring, or a 5- to 6-membered monocyclic heteroaryl ring with 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of them is optional. It may be replaced;
k is 0, 1 or 2;
n is 0, 1, or 2;
p is 0, 1, or 2;
r is 1, 2, or 3; and t is 1, 2, or 3.
Here, the compound, wherein k is 0 when linked to nitrogen and 1 or 2 when linked to carbon. The compound according to claim 1, wherein the ring A is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, or triazineyl. Ring A

The compound according to claim 1 or 2. Ring B is pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, pyrrole, imidazole, isoxazole, oxazole, or thiazole; each of which may be optionally substituted, any one of claims 1-3. The compounds described in the section. Ring B is

The compound according to any one of claims 1 to 4. Ring B is

The compound according to any one of claims 1 to 5. Each R ⁴ is independently C _1-6 aliphatic, -OR, -C (O) R, -CO ₂ R, -C (O) N (R) ₂ , -NRC (O) R, -NRC. (O) OR, -NRC (O) N (R) ₂ , -NRSO ₂ R, or -N (R) ₂ ; each of which may be optionally substituted, claims 1-6. The compound according to any one of the above. Each R ⁴ is independently a C _1-6 aliphatic, -C (O) N (R) ₂ , -NRC (O) R, or -N (R) ₂ ; each of them is optional. The compound according to any one of claims 1 to 7, which may be substituted. Each R ⁴ is independent

The compound according to any one of claims 1 to 8. Each R ⁵ is independently halogen, C _1-6 aliphatic, C _3-10 aryl, 3-8 member saturated or partially unsaturated carbocyclic rings, 1-4 heteroatoms (1-4 heteroatoms). A 3- to 7-membered heterocyclic ring having an independent choice of nitrogen, oxygen, or sulfur, or an independent of 1 to 4 heteroatoms (independently from nitrogen, oxygen, or sulfur). A 5- to 6-membered monocyclic heteroaryl ring having (selected); each of them may be optionally substituted.
The compound according to any one of claims 1 to 9. Each R ⁵ is independently methyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; The compound according to any one of claims 1 to 10, wherein each may be optionally substituted; or each R ⁵ is independently -F, -Cl, -Br, or -I. Formula I-a

The compound according to claim 1, or a pharmaceutically acceptable salt thereof. Formula I-c

The compound according to claim 1, or a pharmaceutically acceptable salt thereof. Equation Id

The compound according to claim 1, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 14, selected from Table 1. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15 and a pharmaceutically acceptable adjuvant, carrier, or vehicle. The compound according to any one of claims 1 to 15, or a physiologically acceptable salt thereof, which is a method for inhibiting TLR7 / 8 (or a mutant thereof) activity in a patient or in a biological sample. The method comprising the step of administering to the patient or bringing the biological sample into contact with it. A method of treating a TLR7 / 8 mediated disorder in a patient in need thereof, wherein the compound according to any one of claims 1 to 15 or a physiologically acceptable salt thereof is administered to the patient. The method comprising the steps of Disorders are rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, inflammatory Intestinal diseases (Clone's disease and ulcerative colitis), hyper-IgDemia and periodic fever syndrome, cryopyrin-associated periodic syndrome, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset still disease, gout, pseudogout, SAPHO syndrome , Castleman's disease, sepsis, stroke, atherosclerotic arthritis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease, and cancer, according to claim 18. .. A method for treating cancer in a subject, the method comprising administering to the subject a compound according to claim 1 or a physiologically acceptable salt thereof.